CN104736158A - Neuroactive steroid preparations and methods of treating central nervous system disorders - Google Patents

Abstract

Formulations comprising neuroactive steroids, such as allopregnanolone, and optionally cyclodextrins, including beta-cyclodextrins, such as sulfobutylether beta-Cyclodextrin (CAPTISOL). And methods of using the neuroactive steroid formulations in the treatment of central nervous system disorders, such as traumatic brain injury, status epilepticus, and seizures.

Description

Neuroactive steroid preparations and methods of treating central nervous system disorders

technical field

The present invention relates generally to neuroactive steroid formulations, in particular allopregnanolone, for use in the treatment of central nervous system injuries and/or disorders.

Cross References to Related Applications

This application claims priority to U.S.S.N. 61/589,740, filed January 23, 2012, the teachings of which are incorporated herein.

Background technique

Central nervous system (CNS) related disorders include disorders affecting either or both the brain or spinal cord. CNS-related disorders can include, for example, traumatic injuries, such as traumatic brain injury. Traumatic injuries to the CNS are characterized by a physical shock to the central nervous system, eg, traumatic brain injury. Status epilepticus (SE) is another example of a CNS-related disorder, e.g., generalized status epilepticus, early status epilepticus, established status epilepticus, treatment-refractory status epilepticus, super-refractory status epilepticus, Convulsive status epilepticus, eg, complex partial status epilepticus.

Contents of the invention

The present disclosure features, inter alia, the inclusion of a neuroactive steroid (such as isopregnalone) and optionally a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin (sulfobutyl ether β-cyclodextrin). -cyclodextrin), such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as )Compositions. The disclosure also features, inter alia, methods of treating a subject suffering from a central nervous system disorder such as traumatic brain injury, status epilepticus such as refractory convulsive status epilepticus, nonconvulsive status epilepticus, the method comprising administering to a subject a composition described herein, such as a neuroactive steroid (such as isopregnalone) and optionally a cyclodextrin (such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ).

In one aspect, the disclosure features a composition comprising a neuroactive steroid such as isopregnolone and a cyclodextrin, e.g., a neuroactive steroid such as isopregnolone and optionally a cyclodextrin Dextrins (such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complexes. (β-cyclodextrin such as sulfobutyl ether β-cyclodextrin, such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complexes.

In some embodiments, the neuroactive steroid is a progesterone derivative, such as isopregnolone. In one embodiment, the neuroactive steroid is isopregnalone.

In some embodiments, the cyclodextrin is β-cyclodextrin. In one embodiment, the cyclodextrin is sulfobutyl ether beta-cyclodextrin. In one embodiment, the cyclodextrin is In some embodiments, the cyclodextrin is β-cyclodextrin, which is disclosed in US Patent Nos. 5,874,418; 6,046,177; or 7,635,733, which are incorporated herein by reference.

In some embodiments, the neuroactive steroid is a progesterone derivative, eg, isopregnalone, and the cyclodextrin is beta-cyclodextrin. In one embodiment, the neuroactive steroid is isopregnalone and the cyclodextrin is

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complexes formulated for parenteral administration. exist

In one embodiment, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg/mL, 10-30mg /mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL, 10-20mg/mL , 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5-10mg/mL; 10 -15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; 5-15mg/mL; 7-12mg/mL; /mL; 3-5mg/mL; or 3-4mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids included in the aqueous composition is 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL; 3.0mg/mL; 3.5mg/mL; /mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is formulated as an aqueous composition, and the aqueous composition includes a neuroactive steroid at a concentration of 1.5 mg/mL. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is formulated as an aqueous composition, and the concentration of the neuroactive steroid included in the aqueous composition is 5 mg/mL. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is formulated as an aqueous composition, and the aqueous composition includes a neuroactive steroid at a concentration of 15 mg/mL.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; ; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL; In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 60mg/ml. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30% , 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10% , 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as The concentration is 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15% , 20%, 25%, 30%, 35% or 40%. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is prepared as an aqueous composition, and the aqueous composition includes 6% cyclodextrin. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is prepared as an aqueous composition, and the aqueous composition includes 15% cyclodextrin. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is prepared as an aqueous composition, and the aqueous composition includes 30% cyclodextrin.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; /mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; /mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; ; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL;

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; /mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as The concentration is 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6- 30%, 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3- 10%, 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; /mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as The concentration is 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15% , 20%, 25%, 30%, 35% or 40%.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and cyclodextrins such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as 25mg/mL; 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL; 300mg/mL; 350mg/mL or 400mg/mL.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and cyclodextrins such as The concentration is 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6- 30%, 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3- 10%, 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and cyclodextrins such as The concentration is 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15% , 20%, 25%, 30%, 35% or 40%.

In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 6%. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 6%. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 6%.

In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 15%. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 15%. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 15%.

In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 30%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 30%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 30%.

In some embodiments, isopregnalone and The complex of is formulated as an aqueous composition having a pH of 3-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-9, 5-8, 5-7, 5-6, 4.5-7.5, or 5.5-7.5. In some embodiments, isopregnalone and The complex of is formulated as an aqueous composition having a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9. In one embodiment, isopregnalone and The complex of is formulated as an aqueous composition having a pH of about 6.

In one aspect, the disclosure features a composition comprising a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin Alginates such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ), wherein the composition includes less than 100 ppm of phosphate (phosphate), and the cyclodextrin (such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin, such as β-cyclodextrin Dextrins such as sulfobutyl ether β-cyclodextrins such as ) has an absorption value lower than 0.2 AU, which is due to drug degrading agents, measured according to a UV/Vis spectrophotometer at a wavelength of 245 nm to 270 nm for a cyclodextrin including 300 mg (such as β - Cyclodextrins such as sulfobutyl ether β-cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) in an aqueous solution with a path length of 1 cm per mL of solution in a cuvette.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) has an absorption value lower than 0.2AU, which is due to the color former, and is measured according to a UV/Vis spectrophotometer at a wavelength of 320nm to 350nm for a cyclodextrin containing 500mg (such as β- Cyclodextrin such as sulfobutyl ether β-cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) in an aqueous solution with a path length of 1 cm per mL of solution in the cuvette.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) further includes less than 20 ppm sulfoalkylating agent; less than 0.5 wt.% underivatized cyclodextrin; less than 1 wt.% alkali metal halide salt; and less than 0.25 wt.% hydrolyzed sulfo alkylating agent.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) has an absorption value lower than 0.2AU, which is due to drug degrading agents, and is measured according to a UV/Vis spectrophotometer at a wavelength of 245nm to 270nm, which is measured for 500 mg of cyclodextrin (such as β- Cyclodextrins such as sulfobutyl ether β-cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) in an aqueous solution with a path length of 1 cm per mL of solution in the cuvette.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) further includes: less than 50 ppm phosphate; less than 10 ppm sulfoalkylating agent; less than 0.2 wt.% underivatized cyclodextrin; less than 0.5 wt.% alkali metal halide salt; and Less than 0.1 wt.% hydrolyzed sulfoalkylating agent; and wherein cyclodextrin (such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin, such as β-cyclodextrin such as Ether β-cyclodextrin such as ) has an absorption value lower than 0.2AU, which is due to the color former, measured according to a UV/Vis spectrophotometer at a wavelength of 320nm to 350nm for a cyclodextrin containing 500mg (such as β- Cyclodextrins such as sulfobutyl ether β-cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ), each mL of solution in the cuvette has a path length of 1 cm.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) further includes: less than 10 ppm phosphate; less than 2 ppm sulfoalkylating agent; less than 0.1 wt.% underivatized cyclodextrin; less than 0.2 wt.% alkali metal halide salt; and Less than 0.08 wt.% of hydrolyzed sulfoalkylating agents; and wherein cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as Ether β-cyclodextrin such as ) has an absorption value lower than 0.1 AU, which is due to the color former, measured according to a UV/Vis spectrophotometer at a wavelength of 320nm to 350nm for a cyclodextrin containing 500mg (such as β- Cyclodextrins such as sulfobutyl ether β-cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ), each mL of solution in the cuvette has a path length of 1 cm.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) further includes: less than 5 ppm phosphate; less than 0.1 wt.% alkali metal halide salt; and less than 0.05 wt.% hydrolyzed sulfoalkylating agent.

In some embodiments, the neuroactive steroid is a progesterone derivative, eg, isopregnalone. In one embodiment, the neuroactive steroid is isopregnalone.

In some embodiments, the cyclodextrin is β-cyclodextrin. In one embodiment, the cyclodextrin is sulfobutyl ether beta-cyclodextrin. In one embodiment, the cyclodextrin is In some embodiments, the cyclodextrin is a beta-cyclodextrin as disclosed in US Patent Nos. 5,874,418, 6,046,177, and 7,635,733, which are incorporated herein by reference.

In some embodiments, the neuroactive steroid is a progestin derivative, eg, isopregnalone, and the cyclodextrin is β-cyclodextrin. In one embodiment, the neuroactive steroid is isopregnalone and the cyclodextrin is

In some embodiments, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complexes formulated for parenteral administration. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg/mL, 10-30mg /mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL, 10-20mg/mL , 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5-10mg/mL; 10 -15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; 5-15mg/mL; 7-12mg/mL; /mL; 3-5mg/mL; or 3-4mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids included in the aqueous composition is 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL; 3.0mg/mL; 3.5mg/mL; /mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is formulated as an aqueous composition, and the aqueous composition includes a neuroactive steroid at a concentration of 1.5 mg/mL. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is formulated as an aqueous composition, and the concentration of the neuroactive steroid included in the aqueous composition is 5 mg/mL. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is formulated as an aqueous composition, and the aqueous composition includes a neuroactive steroid at a concentration of 15 mg/mL.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; ; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL; In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 60mg/ml. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30% , 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10% , 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20 %, 25%, 30%, 35% or 40%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) compound is formulated as an aqueous composition, and the cyclodextrin included in the aqueous composition is 6%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is prepared as an aqueous composition, and the aqueous composition includes 15% cyclodextrin. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is prepared as an aqueous composition, and the aqueous composition includes 30% cyclodextrin.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; ; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL;

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; /mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30% , 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10% , 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; /mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20 %, 25%, 30%, 35% or 40%.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; ; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL;

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30% , 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10% , 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20 %, 25%, 30%, 35% or 40%.

In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 6%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 6%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 6%.

In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 15%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 15%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 15%.

In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 30%. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 30%. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 30%.

In some embodiments, isopregnalone and The complex of is formulated as an aqueous composition having a pH of 3-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-9, 5-8, 5-7, 5-6, 4.5-7.5, or 5.5-7.5. In some embodiments, isopregnalone and The complex of is formulated as an aqueous composition having a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9. In one embodiment, isopregnalone and The complex of is formulated as an aqueous composition having a pH of about 6.

In one aspect, the disclosure features a method of treating a subject suffering from a central nervous system disorder, such as traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early stage epilepsy Status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; nonconvulsive status epilepticus, eg, generalized status epilepticus, complex partial status epilepticus; generalized status epilepticus Periodic epileptiform discharges; periodic unilateral epileptiform discharges; seizures such as acute recurrent seizures, cluster seizures, the method comprising administering a neuroactive steroid to the subject.

In some embodiments, the neuroactive steroid is a progesterone derivative, eg, isopregnalone. In one embodiment, the neuroactive steroid is isopregnalone.

In some embodiments, the central nervous system disorder is traumatic brain injury. In some embodiments, the central nervous system disorder is status epilepticus, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; nonconvulsive Status epilepticus such as generalized status epilepticus, complex partial status epilepticus; systemic periodic epileptiform discharges; periodic one-sided epileptiform discharges. In some embodiments, the central nervous system disorder is traumatic brain injury. In some embodiments, the central nervous system disorder is seizures such as acute recurrent seizures, cluster seizures.

In one embodiment, the disclosure features a method of treating a subject with a status epilepticus, such as refractory convulsive status epilepticus, non-convulsive status epilepticus, comprising administering isopregnal Ketones are administered to the subject. In one embodiment, the disclosure features a method of treating a subject with traumatic brain injury comprising administering isopregnalone to the subject.

In one aspect, the disclosure features a method of treating a subject suffering from a central nervous system disorder, such as traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early stage epilepsy Status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; nonconvulsive status epilepticus, eg, generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; periodic unilateral epileptiform discharges; seizures such as acute recurrent seizures, clustered seizures, the method includes the administration of neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether beta-cyclodextrin, such as beta-cyclodextrin such as sulfobutyl ether beta-cyclodextrin such as ) complex is administered to the subject.

In some embodiments, the neuroactive steroid is a progesterone derivative, eg, isopregnalone. In one embodiment, the neuroactive steroid is isopregnalone.

In some embodiments, the cyclodextrin is β-cyclodextrin. In one embodiment, the cyclodextrin is sulfobutyl ether beta-cyclodextrin. In one embodiment, the cyclodextrin is

In some embodiments, the neuroactive steroid is a progesterone derivative, eg, isopregnalone, and the cyclodextrin is beta-cyclodextrin. In one embodiment, the neuroactive steroid is isopregnalone and the cyclodextrin is

In some embodiments, the central nervous system disorder is traumatic brain injury. In some embodiments, the central nervous system disorder is status epilepticus, convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; nonconvulsive Status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; periodic unilateral epileptiform discharges. In some embodiments, the central nervous system disorder is traumatic brain injury. In some embodiments, the central nervous system disorder is seizures such as acute recurrent seizures, cluster seizures.

In one embodiment, the disclosure features a method of treating a subject suffering from traumatic brain injury comprising administering isopregnalone and The complex is administered to a subject. In one embodiment, the disclosure features a method of treating a subject suffering from status epilepticus, convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, difficult Treatable status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus, the method comprising isopregnolone and The complex is administered to the subject. In one embodiment, the disclosure features a method of treating a subject suffering from epileptic seizures, such as acute recurrent epileptic seizures, epileptic seizures, comprising administering isopregnalone and The complex is administered to a subject.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulation for parenteral administration. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg/mL, 10-30mg /mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL, 10-20mg/mL , 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5-10mg/mL; 10 -15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; 5-15mg/mL; 7-12mg/mL; /mL; 3-5mg/mL; or 3-4mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids included in the aqueous composition is 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL; 3.0mg/mL; 3.5mg/mL; /mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL or 30mg/mL. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is formulated as an aqueous composition, and the aqueous composition includes a neuroactive steroid at a concentration of 1.5 mg/mL. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is formulated as an aqueous composition, and the concentration of the neuroactive steroid included in the aqueous composition is 5 mg/mL. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is formulated as an aqueous composition, and the aqueous composition includes a neuroactive steroid at a concentration of 15 mg/mL.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; ; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL; In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 60mg/ml. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30% , 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10% , 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20 %, 25%, 30%, 35% or 40%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) compound is formulated as an aqueous composition, and the cyclodextrin included in the aqueous composition is 6%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is prepared as an aqueous composition, and the aqueous composition includes 15% cyclodextrin. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is prepared as an aqueous composition, and the aqueous composition includes 30% cyclodextrin.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25mg/mL; 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; ; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL;

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; /mL; 8-9mg/mL; 3-5mg/mL; or3-4mg/mL; and cyclodextrins such as 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30% , 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10% , 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; /mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20 %, 25%, 30%, 35% or 40%.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; ; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL;

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30% , 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10% , 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20 %, 25%, 30%, 35% or 40%.

In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 6%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 6%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 6%.

In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 15%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 15%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 15%.

In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 30%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 30%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 30%.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition having a pH of 3-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-9, 5-8, 5-7, 5-6, 4.5-7.5, or 5.5-7.5. In some embodiments, isopregnalone and The complex of is formulated as an aqueous composition having a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9. In one embodiment, isopregnalone and The complex of is formulated as an aqueous composition having a pH of about 6.

In some embodiments, isopregnanolone and The complex is formulated as an aqueous composition and administered intravenously. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered intramuscularly.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered for 1-10, 1-5, 5-10, 1-6, 2-6, 3-6, 4-5 or 1-9 consecutive days. In one embodiment, isopregnalone and The complex was formulated as an aqueous composition and administered for 5 consecutive days. In some embodiments, the duration of administration is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, the duration of administration is 3-7, 4-6, 4-5, or 5-6 days. In some embodiments, the duration of administration is 5 days.

In some embodiments, isopregnalone and The complexes are formulated as aqueous compositions and administered at the same dose for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered as a loading dose such as a bolus injection dose for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days, followed by a maintenance dose such as an infusion dose. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In one embodiment, isopregnalone and The complex is formulated as an aqueous composition, and at 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL ;4.0mg/mL;4.5mg/mL;5.0mg/mL,5.5mg/mL,6.0mg/mL,6.5mg/mL,7.0mg/mL,7.5mg/mL,8.0mg/mL,8.5mg/mL , 9.0 mg/mL, 9.5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg.mL, or 30 mg/mL of a neuroactive steroid such as isopregnalone loading dose as a bolus injection1 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5 mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5 A maintenance dose of mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg.mL or 30 mg/mL neuroactive steroid such as isopregnalone is administered as an infusion dose for 3 consecutive days. In some embodiments, maintenance doses, eg, infusion doses, described herein are lower than loading doses, eg, bolus doses, described herein. In some embodiments, maintenance doses, such as infusion doses, are lower than 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5 mg/mL; 3.0 mg/mL; 3.5 mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5 mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL or 30mg/mL.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered as a loading dose such as a bolus injection for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days, followed by a maintenance dose such as an infusion 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, followed by gradually decreasing doses of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered as a loading dose such as a bolus injection for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days, followed by a maintenance dose such as an infusion 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, followed by first tapered doses of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 hours.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered as a loading dose such as a bolus injection for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days, followed by a maintenance dose such as an infusion Dosing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, followed by 1, 2, 3, 4, 5, 6, 7, 8 in first tapered doses , 9 or 10 hours, followed by a second tapering dose for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 hours. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered as a loading dose such as a bolus injection for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days, followed by a maintenance dose such as an infusion 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, followed by first tapered doses of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours, followed by a second tapered dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours, followed by a third tapered dose of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 hours.

In some embodiments, the first, second or third tapered dose is lower than the maintenance dose, eg, the infused dose. In some embodiments, the second tapered dose or the third tapered dose is lower than the first tapered dose. In some embodiments, the third tapered dose is lower than the second tapered dose. In some embodiments, the first tapered dose is a maintenance dose such as 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%. In some embodiments, the first tapered dose is a maintenance dose, eg, 95-50%, 75-50%, 85-50%, 90-50%, 80-50%, or 75-100% of the infused dose. In one embodiment, the first tapered dose is 75% of the maintenance dose, eg, the infused dose.

In some embodiments, the second tapered dose is a maintenance dose such as 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%. In some embodiments, the second tapered dose is a maintenance dose such as 95-30%, 75-30%, 85-30%, 60-30%, 70-30%, 50-30% or 50-40%. In one embodiment, the second tapered dose is 50% of the maintenance dose, eg, the infused dose.

In some embodiments, the third tapering dose is a maintenance dose such as 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%. In some embodiments, the third tapering dose is a maintenance dose such as 50-5%, 40-5%, 30-5%, 25-5%, 25-10%, 25-20% or 25-40%. In one embodiment, the second tapered dose is 50% of the maintenance dose, eg, the infused dose. In one embodiment, the third tapered dose is 25% of the maintenance dose, eg, the infused dose.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered in doses required to achieve a predetermined burst suppression pattern such as inter-burst intervals (inter-burst intervals) of 2-30 seconds; the burst suppression pattern is monitored by neurophysiological monitoring ( Neurophysiological monitoring) methods such as EEG, CFM determined. In some embodiments, isopregnalone and The compound is formulated as an aqueous composition, and to achieve a predetermined pulse suppression mode such as 2-30 seconds, 5-30 seconds, 10-30 seconds, 15-30 seconds, 1-30 seconds, 0-30 seconds, 2- 20 seconds, 2-10 seconds, 5-20 seconds, 10-20 seconds, 15-25 seconds, 5-15 seconds, or 5-10 seconds between pulse intervals required for dosing; the pulse suppression mode is determined by Methods of nerve electrophysiological monitoring such as EEG, CFM determined.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and within 48 hours, 24 hours, 20 hours, 18 hours, 16 hours, 10 hours, 8 hours, 5 hours, 3 hours, 1 hour or 0.5 hours after traumatic brain injury medication. In one embodiment, isopregnalone and The complex of ® was formulated as an aqueous composition and administered within 10 hours after traumatic brain injury. In one embodiment, isopregnalone and The complex was formulated as an aqueous composition and administered within 8 hours after traumatic brain injury.

In some embodiments, isopregnalone and Formulated as an aqueous composition and administered within 10 hours, 8 hours, 5 hours, 3 hours, 1 hour, or 0.5 hours after an epileptic seizure, such as a status epilepticus seizure, such as a refractory status epilepticus seizure, has started medication. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered within 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes after an epileptic seizure, such as a status epilepticus seizure, such as a refractory status epilepticus seizure, has started. In some embodiments, isopregnalone and The complex of is formulated as an aqueous composition and administered after an epileptic seizure, such as a status epilepticus seizure, such as a refractory status epilepticus seizure, lasts for 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes or 60 minutes.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and is administered prior to the onset of an epileptic seizure, such as a status epilepticus seizure, such as a seizure in refractory status epilepticus.

In one aspect, the disclosure features: a method of treating a subject with a central nervous system disorder, such as traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus Status, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; nonconvulsive status epilepticus, eg, generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges ; Periodic unilateral epileptiform discharges; Seizures such as acute recurrent seizures, intensive seizures, the method includes the administration of neuroactive steroids (such as isopregnolone) and cyclodextrins (such as β-cyclodextrins such as sulfonic acid Butyl ether beta-cyclodextrin, such as beta-cyclodextrin, such as sulfobutyl ether beta-cyclodextrin, such as ) complex is administered to the subject, wherein the composition includes less than 100 ppm of phosphate, and cyclodextrin (such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin, such as β- Cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) has an absorption value lower than 0.2 AU, which is due to the drug degrading agent, and is measured according to a UV/Vis spectrophotometer at a wavelength of 245nm to 270nm for a cyclodextrin including 300mg (such as β- Cyclodextrins such as sulfobutyl ether β-cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ), each mL of solution in the cuvette has a path length of 1 cm.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) has an absorption value lower than 0.2AU, which is due to the color former, and is measured according to a UV/Vis spectrophotometer at a wavelength of 320nm to 350nm for a cyclodextrin containing 500mg (such as β- Cyclodextrin such as sulfobutyl ether β-cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) in aqueous solution with a path length of 1 cm per mL of solution in the cuvette.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) further includes: less than 20 ppm of sulfoalkylating agents; less than 0.5% wt. of underivatized cyclodextrins; less than 1% wt. of alkali metal halide salts; and less than 0.25% wt. of Hydrolyzed sulfoalkylating agent.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) has an absorption value lower than 0.2AU, which is due to drug degrading agents, and is measured according to a UV/Vis spectrophotometer at a wavelength of 245nm to 270nm, which is measured for cyclodextrins including 500mg (such as β- Cyclodextrin such as sulfobutyl ether β-cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) in aqueous solution with a path length of 1 cm per mL of solution in the cuvette.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) includes: less than 50 ppm phosphate; less than 10 ppm sulfoalkylating agent; less than 0.2% wt. underivatized cyclodextrin; less than 0.5% wt. alkali metal halide salt; Hydrolyzed sulfoalkylating agent at 0.1% wt.; and wherein cyclodextrin (such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin, such as β-cyclodextrin such as sulfobutyl Ether β-cyclodextrin as ) has an absorption value lower than 0.2AU, which is due to the color former, and is measured according to a UV/Vis spectrophotometer at a wavelength of 320nm to 350nm for a cyclodextrin containing 500mg (such as β- Cyclodextrin such as sulfobutyl ether β-cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) in aqueous solution with a path length of 1 cm per mL of solution in the cuvette.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) includes: less than 10 ppm phosphate; less than 2 ppm sulfoalkylating agent; less than 0.1% wt. underivatized cyclodextrin; less than 0.2% wt. alkali metal halide salt; Hydrolyzed sulfoalkylating agents at 0.08% wt.; and wherein cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl Ether β-cyclodextrin as ) has an absorption value lower than 0.1 AU, which is due to the color former, measured according to a UV/Vis spectrophotometer at a wavelength of 320nm to 350nm, which is measured for a cyclodextrin containing 500mg (such as β- Cyclodextrin such as sulfobutyl ether β-cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) in aqueous solution with a path length of 1 cm per mL of solution in the cuvette.

In some embodiments, cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins, such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) includes: less than 5 ppm phosphate; less than 0.1% wt. alkali metal halide salt; and less than 0.05% wt. hydrolyzed sulfoalkylating agent.

In some embodiments, the central nervous system disorder is traumatic brain injury. In some embodiments, the central nervous system disorder is status epilepticus, convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; nonconvulsive Status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; periodic unilateral epileptiform discharges. In some embodiments, the central nervous system disorder is traumatic brain injury. In some embodiments, the central nervous system disorder is seizures such as acute recurrent seizures, cluster seizures.

In one embodiment, the disclosure features a method of treating a subject suffering from traumatic brain injury comprising administering isopregnalone and The complex is administered to a subject. In one embodiment, the disclosure features a method of treating a subject suffering from status epilepticus, convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus , refractory status epilepticus, super-refractory status epilepticus; nonconvulsive status epilepticus, eg, generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; periodic unilateral seizures like discharge, the method includes the isopregnanolone and The complex is administered to a subject. In one embodiment, the disclosure features a method of treating a subject having seizures, such as acute recurrent seizures, intensive seizures, comprising administering isopregnal Keto and The complex is administered to a subject.

In some embodiments, the neuroactive steroid is a progesterone derivative, eg, isopregnalone. In one embodiment, the neuroactive steroid is isopregnalone.

In some embodiments, the cyclodextrin is β-cyclodextrin. In one embodiment, the cyclodextrin is sulfobutyl ether beta-cyclodextrin. In one embodiment, the cyclodextrin is In some embodiments, the cyclodextrin is a beta-cyclodextrin as disclosed in US Pat. Nos. 5,874,418, 6,046,177, and 7,635,733, which are incorporated herein by reference.

In some embodiments, the neuroactive steroid is a progesterone derivative, eg, isopregnalone, and the cyclodextrin is beta-cyclodextrin. In one embodiment, the neuroactive steroid is isopregnalone and the cyclodextrin is

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complexes formulated for parenteral administration. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg/mL, 10-30mg /mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL, 10-20mg/mL , 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5-10mg/mL; 10 -15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; 5-15mg/mL; 7-12mg/mL; /mL; 3-5mg/mL; or 3-4mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids included in the aqueous composition is 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL; 3.0mg/mL; 3.5mg/mL; /mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is formulated as an aqueous composition, and the aqueous composition includes a neuroactive steroid at a concentration of 1.5 mg/mL. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is formulated as an aqueous composition, and the concentration of the neuroactive steroid included in the aqueous composition is 5 mg/mL. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is prepared as an aqueous composition, and the aqueous composition includes a neuroactive steroid at a concentration of 15 mg/mL.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; ; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL; In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 60mg/ml. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30% , 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10% , 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) complex formulated as an aqueous composition comprising cyclodextrins such as 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20 %, 25%, 30%, 35% or 40%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) compound is formulated as an aqueous composition, and the cyclodextrin included in the aqueous composition is 6%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is prepared as an aqueous composition, and the aqueous composition includes 15% cyclodextrin. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex is prepared as an aqueous composition, and the aqueous composition includes 30% cyclodextrin.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; ; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL;

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; /mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30% , 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10% , 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, the concentration of neuroactive steroids such as isopregnanolone included in the aqueous composition is 0.25-30mg/mL, 0.5-30mg/mL; 1-30mg/mL; 5-30mg /mL, 10-30mg/mL; 15-30mg/mL, 0.25-20mg/mL; 0.5-20mg/mL; 1-20mg/mL, 0.5-20mg/mL; 1-20mg/mL, 5-20mg/mL , 10-20mg/mL, 0.25-15mg/mL, 0.5-15mg/mL; 0.5-10mg/mL; 1-15mg/mL, 1-10mg/mL; 1-5mg/mL; 5-15mg/mL; 5 -10mg/mL; 10-15mg/mL; 1-10mg/mL; 2-8mg/mL; 2-7mg/mL; 3-5mg/mL; /mL; 8-9mg/mL; 3-5mg/mL; or 3-4mg/mL; and cyclodextrins such as 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20 %, 25%, 30%, 35% or 40%.

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as The concentration is 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25-50mg/mL; 50-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200-300mg/mL; 200-400mg/mL; -75 mg/mL; 50-70 mg/mL; 55-65 mg/mL; or 50-60 mg/mL. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as 30mg/mL; 35mg/mL; 40mg/mL; 45mg/mL; 50mg/mL; 55mg/mL; 60mg/mL; 65mg/mL; 70mg/mL; ; 85mg/mL; 90mg/mL, 95mg/mL; 100mg/mL; 150mg/mL; 200mg/mL; 250mg/mL;

In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as 2.5-40%, 2.5-30%, 2.5-20%, 2.5-10%, 5-40%, 5-30%, 5-20%, 5-10%, 6-40%, 6-30% , 6-20%, 6-10%, 10-40%, 10-30%, 10-20%, 20-40%, 20-30%, 25-40%, 25-30%, 3-10% , 4.5-7.5%, 5-7%, 5.5-6.5%. In some embodiments, neuroactive steroids (such as isopregnalone) and cyclodextrins (such as β-cyclodextrins such as sulfobutyl ether β-cyclodextrins such as ) compound is formulated as an aqueous composition, and the concentration of neuroactive steroids such as isopregnalone included in the aqueous composition is 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; 4.0mg/mL; 4.5mg/mL; mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL, or 30mg/mL; and Cyclodextrins such as 2.5%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20 %, 25%, 30%, 35% or 40%.

In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 6%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 6%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 6%.

In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 15%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 15%. In one embodiment, a neuroactive steroid (such as isopregnalone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 15%.

In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 1.5 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β-cyclodextrin as The concentration is 30%. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 10 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 30%. In one embodiment, a neuroactive steroid (such as isopregnolone) and a cyclodextrin (such as a β-cyclodextrin such as sulfobutyl ether β-cyclodextrin such as ) complex formulated as an aqueous composition comprising a neuroactive steroid such as isopregnalone at a concentration of 15 mg/mL, and a cyclodextrin such as β-cyclodextrin such as sulfobutyl ether β - Cyclodextrins such as The concentration is 30%.

In some embodiments, isopregnalone and The complex of is formulated as an aqueous composition having a pH of 3-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-9, 5-8, 5-7, 5-6, 4.5-7.5, or 5.5-7.5. In some embodiments, isopregnalone and The complex of is formulated as an aqueous composition having a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9. In one embodiment, isopregnalone and The complex of is formulated as an aqueous composition having a pH of about 6.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered intravenously. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered intramuscularly.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered for 1-10, 1-5, 5-10, 1-6, 2-6, 3-6, 4-5 or 1-9 consecutive days. In one embodiment, isopregnalone and The complex was formulated as an aqueous composition and administered for 5 consecutive days. In some embodiments, the duration of administration is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, the duration of administration is 3-7, 4-6, 4-5, or 5-6 days. In some embodiments, the duration of administration is 5 days.

In some embodiments, isopregnalone and The complex was formulated as an aqueous composition and administered at the same dose for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered as a loading dose such as a bolus injection for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days, followed by a maintenance dose such as an infusion Doses are administered for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days. In one embodiment, isopregnalone and The complex is formulated as an aqueous composition, and at 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL ;4.0mg/mL;4.5mg/mL;5.0mg/mL,5.5mg/mL,6.0mg/mL,6.5mg/mL,7.0mg/mL,7.5mg/mL,8.0mg/mL,8.5mg/mL , 9.0 mg/mL, 9.5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg.mL or 30 mg/mL neuroactive steroid such as isopregnanolone loading dose administered as a bolus dose for 1 day , then at 0.25mg/mL, 0.5mg/mL; 1.0mg/mL; 1.5mg/mL; 2.0mg/mL; 2.5mg/mL; 3.0mg/mL; 3.5mg/mL; /mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5mg/mL, 9.0mg/mL, 9.5mg A maintenance dose of 1/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg.mL or 30 mg/mL neuroactive steroid such as isopregnalone is administered as an infusion dose for 3 consecutive days. In some embodiments, maintenance doses, eg, infusion doses, described herein are lower than loading doses, eg, bolus doses, described herein. In some embodiments, maintenance doses, such as infusion doses, are lower than 0.25 mg/mL, 0.5 mg/mL; 1.0 mg/mL; 1.5 mg/mL; 2.0 mg/mL; 2.5 mg/mL; 3.0 mg/mL; 3.5 mg/mL; 4.0mg/mL; 4.5mg/mL; 5.0mg/mL, 5.5mg/mL, 6.0mg/mL, 6.5mg/mL, 7.0mg/mL, 7.5mg/mL, 8.0mg/mL, 8.5 mg/mL, 9.0mg/mL, 9.5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg.mL or 30mg/mL.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered as a loading dose such as a bolus injection for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days, followed by a maintenance dose such as an infusion 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, followed by gradually decreasing doses of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered as a loading dose such as a bolus injection for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days, followed by a maintenance dose such as an infusion 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, followed by first tapered doses of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 hours.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered as a loading dose such as a bolus injection for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days, followed by a maintenance dose such as an infusion 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, followed by first tapered doses of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 hours, followed by a second tapering dose for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 hours. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered as a loading dose such as a bolus injection for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive days, followed by a maintenance dose such as an infusion 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, followed by first tapered doses of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours, followed by a second tapered dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours, followed by a third tapered dose of 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 hours.

In some embodiments, the first, second or third tapered dose is lower than the maintenance dose, eg, the infused dose. In some embodiments, the second tapered or third tapered dose is lower than the first tapered dose. In some embodiments, the third tapered dose is lower than the second tapered dose. In some embodiments, the first tapered dose is a maintenance dose such as 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%. In some embodiments, the first tapered dose is a maintenance dose, eg, 95-50%, 75-50%, 85-50%, 90-50%, 80-50%, or 75-100% of the infused dose. In one embodiment, the first tapered dose is 75% of the maintenance dose, eg, the infused dose.

In some embodiments, the second tapered dose is a maintenance dose such as 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%. In some embodiments, the second tapered dose is a maintenance dose such as 95-30%, 75-30%, 85-30%, 60-30%, 70-30%, 50-30% or 50-40%. In one embodiment, the second tapered dose is 50% of the maintenance dose, eg, the infused dose.

In some embodiments, the third tapering dose is a maintenance dose such as 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%. In some embodiments, the third tapering dose is a maintenance dose such as 50-5%, 40-5%, 30-5%, 25-5%, 25-10%, 25-20% or 25-40%. In one embodiment, the second tapered dose is 50% of the maintenance dose, eg, the infused dose. In one embodiment, the third tapered dose is 25% of the maintenance dose, eg, the infused dose.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered in doses required to achieve a predetermined pulse suppression pattern, such as an interpulse interval of 2-30 seconds; said pulse suppression pattern is monitored by neurophysiological methods such as EEG, CFM measured. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition, and is required to achieve a predetermined pulse suppression mode such as 2-30 seconds, 5-30 seconds, 10-30 seconds, 15-30 seconds, 1-30 seconds, 0-30 seconds, 2 - 20 seconds, 2-10 seconds, 5-20 seconds, 10-20 seconds, 15-25 seconds, 5-15 seconds or 5-10 seconds inter-pulse interval required dosing; said pulse suppression mode is Measured by neurophysiological monitoring methods such as EEG, CFM.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and within 48 hours, 24 hours, 20 hours, 18 hours, 16 hours, 10 hours, 8 hours, 5 hours, 3 hours, 1 hour or 0.5 hours after traumatic brain injury medication. In one embodiment, isopregnalone and The complex was formulated as an aqueous composition and administered within 10 hours after traumatic brain injury. In one embodiment, isopregnalone and The complex was formulated as an aqueous composition and administered within 8 hours after traumatic brain injury.

In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered within 10 hours, 8 hours, 5 hours, 3 hours, 1 hour or 0.5 hours after an epileptic seizure, such as a status epilepticus seizure, such as a refractory status epilepticus seizure, has started medicine. In some embodiments, isopregnalone and The complex is formulated as an aqueous composition and administered within 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes after an epileptic seizure, such as a status epilepticus seizure, such as a refractory status epilepticus seizure, has started . In some embodiments, isopregnalone and The complex of is formulated as an aqueous composition and administered after an epileptic seizure, such as a status epilepticus seizure, such as a refractory status epilepticus seizure, lasts for 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes or 60 minutes.

In some embodiments, isopregnalone and The complex of is formulated as an aqueous composition and administered prior to the onset of an epileptic seizure, such as a seizure in status epilepticus, such as a seizure in refractory status epilepticus.

Description of drawings

Figure 1A is a graph depicting the percentage of seizures in fmr1KO mice (3, 10, 30 mg/kg isopregnolone administered intraperitoneally in 30% β-cyclodextrin). histogram. Figure 1B is a bar graph depicting the percent survival in fmr1 KO mice (3, 10, 30 mg/kg isopregnolone administered intraperitoneally in 30% β-cyclodextrin) picture.

Figure 2A is a graph depicting C57BL6/J mice treated at PZT (3, 10, 30 mg/kg isopregnolone administered intraperitoneally in 15% β-cyclodextrin) A graph of seizure grades in . Figure 2B is a graph depicting C57BL6/J mice treated with PZT (3, 10, 30 mg/kg isopregnolone administered intraperitoneally in 15% β-cyclodextrin) The graph of waiting for the death period (latency to death period) in .

Figure 3 is a depiction of a patient (5 days of intravenous administration of 1.5 mg/ml isopregnalone in 6% hydroxypropyl-β-cyclodextrin/0.9% sodium chloride) A graph of the plasma concentration profile.

Figure 4A depicts a single dose of intramuscular (10 mg/kg) or intravenous (5 mg/kg) isopregnalone (at 30% Middle) Isopregnolone plasma exposure profile measured by LC/MS-MS after dosing. Figure 4B depicts a single dose of intramuscular (10 mg/kg) or intravenous (5 mg/kg) isopregnalone (at 30% Middle) Brain exposure profile of isopregnalone measured by LC/MS-MS after dosing.

Figure 5A depicts the effect of progesterone in the low and high dose groups (at 6% Middle) the latency to fallperiod (seconds). Figure 5B depicts the effect of progesterone in the low and high dose groups (at 6% The mean motorscore in (Middle).

detailed description

As used herein, "isopregnolone" also includes pharmaceutically acceptable, pharmacologically effective derivatives, including individual enantiomers (dextro- and levo-enantiomers) and their pharmaceutically acceptable salts , mixtures of enantiomers and their pharmaceutically acceptable salts, and active metabolites and their pharmaceutically acceptable salts, unless otherwise stated. It will be appreciated that in some cases it may be necessary to adjust the dosages of enantiomers, derivatives and metabolites based on the relative activity of the racemic mixture of isopregnalone.

As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid addition or base addition salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those obtained from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and from organic acids such as acetic, propionic, succinic, glycolic, hard Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfamic acid, 2-acetyl Salts prepared from oxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionate.

Delayed Release Dosage Form: A delayed release dosage form is a dosage form that releases one or more drugs for a different time than a dosage form that releases it immediately after administration.

Extended release dosage form: An extended release dosage form is a dosage form that allows at least a two-fold reduction in dosing frequency compared to a drug prepared as a conventional dosage form, such as a solution or a conventional solid dosage form of an immediate release drug.

Modified Release Dosage Form: A modified release dosage form is one in which the timing, course, and/or location of drug release are selected to achieve a therapeutic or convenience goal not provided by conventional dosage forms such as solutions, ointments, or fast-dissolving forms. Delayed-release and extended-release dosage forms and combinations thereof are types of modified release dosage forms.

Matrix-Forming Materials: Matrix-forming materials are materials that form strong, viscous gels when hydrated and provide control over drug diffusion and release. In hydrophilic matrix systems, the matrix forming material is incorporated uniformly throughout the tablet. When in contact with water, the outer layer of the tablet undergoes partial hydration, thereby forming a gel layer. The rate of drug diffusion out of the gel layer and the rate of gel layer erosion determine the overall tablet dissolution and drug release rate. Examples of matrix-forming materials include water-soluble cellulose ethers such as methylcellulose, ethylcellulose, and hydroxypropylmethylcellulose.

"Alkyl" as used herein refers to a saturated or unsaturated aliphatic group, including straight chain alkyl, alkenyl or alkynyl, branched chain alkyl, alkenyl or alkynyl, ring Alkyl, cycloalkenyl or cycloalkynyl (cycloaliphatic) groups, alkyl substituted cycloalkyl, cycloalkenyl or cycloalkynyl and cycloalkyl substituted alkyl, alkenyl or alkynyl. Unless otherwise specified, straight or branched chain alkyl groups have 30 or fewer carbon atoms in their backbone (e.g., C ₁ -C ₃₀ for straight chains, C ₃ -C ₃₀ for branched chains), more Preferably 20 or fewer carbon atoms, more preferably 12 or fewer carbon atoms and most preferably 8 or fewer carbon atoms. In certain embodiments, the alkyl group contains 1 to 6, more preferably 1 to 4 carbon atoms. Likewise, preferred cycloalkyl groups have 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure. The ranges provided above are inclusive of all values ranging from the minimum value to the maximum value.

Alkyl groups may also be substituted with one or more groups including, but not limited to, halogen, hydroxyl, amino, thio, ether, ester, carboxy, oxo, and aldehyde. Alkyl groups may also contain one or more heteroatoms within the carbon backbone. The heteroatoms introduced into the carbon backbone are preferably oxygen, nitrogen, sulfur and combinations thereof. In certain embodiments, alkyl groups contain one to four heteroatoms.

As used herein, "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups containing or including one or more double bonds or triple bonds, the length (eg C ₂ -C ₃₀ ) and possible Substitution is similar to alkyl as described above.

As used herein, "heterocycle" or "heterocyclic" refers to a cyclic group linked via a monocyclic or bicyclic ring carbon or ring nitrogen, which contains or includes 3-10 ring atoms, and preferably 5 -6 ring atoms consisting of carbon and one to four heteroatoms each selected from non-peroxide oxygen, sulfur and N(Y), where Y is absent or H, O, (C _1-4 ) Alkyl, phenyl or benzyl, said cyclic group optionally containing or including one or more double or triple bonds, and optionally substituted with one or more substituents. The term "heterocycle" also includes substituted and unsubstituted heteroaromatic rings. Examples of heterocycles include, but are not limited to, benzimidazolyl, benzofuryl, benzothiofuryl, benzothienyl, benzooxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolyl, Triazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromene cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furyl, furanyl, imidazolidinyl , imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indorazinyl, indolyl, 3H-indolyl, isatoyl, isobenzofuryl, iso Chromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl , octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthroline, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl , Phthalazinyl, piperazinyl, piperidinyl, piperidinonyl, 4-piperidinonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazole Linyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridimidazolyl, pyridothiazolyl, pyridinyl (pyridinyl), pyridyl (pyridyl), pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrofuryl Azolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, thianthranyl, thiazolyl, thienyl (thienyl), thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl (xanthenyl) ).

"Halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

As used herein, the term "substituted" refers to all permissible substituents of the compounds described herein. In a broad sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic group (containing or comprising any number of carbon atoms, preferably 1-14 carbon atoms, and optionally including one or more heteroatoms such as oxygen, sulfur or nitrogen, in the form of linear, branched or cyclic structures). Representative substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted Heteroaryl, halogen, hydroxy, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aryloxy, substituted aryloxy, alkylthio, substituted alkylthio, benzene Thio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, Amino, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphono, substituted phosphono, polyaryl, substituted polyaryl, C ₃ -C ₂₀ Cyclic groups, substituted C3 _{- C20} cyclic groups, heterocyclic groups, substituted heterocyclic groups, amino acid, peptide and polypeptide groups.

Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. It should be understood that "substituted" or "substituted" includes the implied proviso that these substitutions are based on the valence states permitted by the atoms being substituted and the substituents, and that the substitutions result in stable compounds, i.e., will not , Elimination, etc. and spontaneous transformation of the compound.

A therapeutically effective treatment is one that achieves relief of one or more symptoms of injury such as improved morphological recovery (ie, enhanced tissue activity) and/or behavioral recovery. The improvement may be characterized as an increase in the rate and/or extent of behavioral recovery and/or anatomical recovery following traumatic central nervous system injury. Neurodegenerative diseases are the progressive loss of neurons in the central nervous system. As used herein, "neuroprotection" is the arrest and/or reversal of neurodegenerative disease following traumatic central nervous system injury. A variety of physiological events lead to neurodegenerative diseases of central nervous system tissue following traumatic central nervous system injury. These events include, for example: cerebral edema, disruption of vascular integrity, increases in immune and inflammatory responses, demyelination and lipid peroxidation. The preparation can be used to reduce and/or prevent physiological activities leading to neurodegenerative diseases after traumatic injury to the central nervous system, including reducing or eliminating neuronal cell death, edema, ischemia and improving tissue activity.

Modified Release Neuroactive Steroid Formulations

A. Neuroactive steroids

Neuroactive steroids (or neurosteroids) are natural, synthetic, or semi-synthetic steroids that rapidly alter neuronal excitability by interacting with neurotransmitter-gated ion channels. Neuroactive steroids act by binding to membrane-bound receptors such as those for inhibitory and/or excitatory neurotransmitters, including _GABAA , NMDA and sigma receptors.

Steroids can be classified into functional groups based on chemical structure and physiological activity and include estrogens, progestins and androgens. Of particular interest are progestins (referred to herein as "progestins" or "progestogens") and their derivatives and biologically active metabolites. Members of this extended family include the steroid hormones disclosed in Remington's Pharmaceutical Sciences, Gennaro et al., Mack Publishing Co. (18th Ed., 1990), 990-993. Stereoisomerism is important with sex hormones, just like with all other types of steroids. Various progestogens as used herein (ie, progesterone) and their derivatives (including synthetic and natural products), as well as progestogen metabolites such as progesterone, can be used.

The term "progesterone" as used herein means a member of the progestin family and includes carbon 21 steroid hormones. Progesterone is also known as D4-pregnene-3,20-dione; Δ4-pregnene-3,20-dione; or pregn-4-ene-3,20-dione. As used herein, a "synthetic progestogen" is a molecule structurally related to progesterone that is obtained synthetically and that retains the biological activity of progesterone (ie, to treat traumatic central nervous system injury).

Representative synthetic progestins include, but are not limited to, modifications to produce 17α- OH ester (i.e. 17α-hydroxyprogesterone caproate), and the introduction of 6-methyl, 6-ene and 6-chloro substituents on progesterone for modification (i.e. methylhydroxyprogesterone acetate, medroxyprogesterone acetate ketone ester and chlormadinone acetate), and it maintains the biological activity of progesterone (ie, the treatment of traumatic central nervous system injury). Such progestin derivatives include 5-dehydroprogesterone, 6-dehydro-retroprogesterone (dydrogesterone), allopregnanolone (allopregnanolone) ene-3α or 3β-alcohol-20-one), ethynodiol diacetate, hydroxyprogesterone caproate (preg-4-ene-3,20-dione, 17-(1 -oxohexyl)oxy); levonorgestrel (levonorgestrel), norethindrone (norethindrone), norethindrone acetate (norethindroneacetate) (19-norpregna-4-ene-20-yne-3 - Ketone (19-norpregn-4-en-20-yn-3-one), 17-(acetoxy)-, (17α)-); norethindrone, norethindrone methyl, pregnenolone (pregnenolone) and megestrol acetate.

Useful progestins may also include allopregnane-3α or 3β, 20α or 20β-diol (see MerckIndex 258-261); allopregnane-3β, 21-diol-11,20-dione; 3β,17α-diol-20-one; 3,20-Poppregnane dione, pippregna-3β,11β,17α,20β,21-pentaol; pippregna-3β,17α,20β,21- Tetrol; Pregnane-3α or 3β, 11β, 17α, 21-tetrol-20-one, Pregnane-3β, 17α or 20β-triol; Pregnane-3β, 17α, 21-triol- 11,20-dione; pippregna-3β,11β,21-triol-20-one; pippregna-3β,17α,21-triol-20-one; pippregna-3α or 3β-ol -20-one; Pregnanediol; 3,20-pregnanedione; Pregnane-3α-ol-20-one; 4-pregnane-20,21-diol-3,11-dione; 4 -pregnene-11β,17α,20β,21-tetrol-3-one; 4-pregnene-17α,20β,21-triol-3,11-dione; 4-pregnene-17α,20β,21 - Triol-3-one and pregnenolone methyl ether. In addition, progesterone derivatives also include esters with non-toxic organic acids such as acetic acid, benzoic acid, maleic acid, malic acid, caproic acid and citric acid and inorganic salts such as hydrochloride, sulfate, nitrate, bicarbonate and carbonates. Other suitable progestogens include alphaxalone, alphadolone, hydroxydione and minaxolone.

Additional suitable neuroactive steroids are disclosed in US Patent Application Publications US 2011/0092473 and US 2010/0317638 and U.S. Patent 5,232,917, which are incorporated herein by reference for the neuroactive steroids described therein.

In certain embodiments, the neuroactive steroid is defined by formula I

in,

R is hydrogen or _an alkyl group, an alkenyl group or an alkynyl group;

R is _hydrogen or an amino, thio, sulfinyl, sulfonyl, halogen, trifluoromethyl, nitro, alkoxy, alkyl, alkenyl or alkynyl group;

R _3a is a hydroxyl group and R _3b is hydrogen or R _3a and R _3b together represent a ketone group;

R4 is hydrogen when the bond between _C4 and C5 and C5 and C6 is a single bond, or when a double bond is present between C4 and C5 of the steroid ring system or between C5 and C6 of the steroid ring system , then R ₄ does not exist;

_R is hydrogen or an alkyl, alkoxy, amino, nitro, hydroxy, halogen, trifluoromethyl, cyano, alkenyl or alkynyl group;

R6 is hydrogen or an alkyl, alkoxy, amino, nitro, hydroxy, halogen, trifluoromethyl, cyano, alkenyl or alkynyl group;

_R is hydrogen or an acetyl, hydroxyacetyl, acyl, alkyl, alkoxy, amino, nitro, halogen, trifluoromethyl, cyano, alkenyl, heterocyclyl or alkynyl group;

_R is hydrogen or an acetyl, hydroxyacetyl, acyl, alkyl, alkoxy, amino, nitro, halogen, trifluoromethyl, cyano, alkenyl, heterocyclyl or alkynyl group;

_R is hydrogen or an acetyl, hydroxyacetyl, acyl, alkyl, alkoxy, amino, nitro, halogen, trifluoromethyl, cyano, alkenyl, heterocyclyl or alkynyl group;

Or R _7b and R ₈ together with the carbon atoms they are attached to form a C3-C7 carbocyclic or heterocyclic ring, which is optionally substituted with one or more selected from hydrogen or acetyl, hydroxyacetyl, acyl, alkyl, alkane Substituents in oxy, amino, nitro, halogen, trifluoromethyl, cyano, alkenyl, heterocyclyl, epoxy or alkynyl groups;

_R is hydrogen or an amino, thio, sulfinyl, nitro, sulfonyl, halogen, alkoxy, alkyl, alkenyl, ketone or alkynyl group;

R ₁₀ is R ₅ is hydrogen or an alkyl, alkoxy, amino, nitro, hydroxy, halogen, trifluoromethyl, cyano, alkenyl or alkynyl group, preferably hydrogen;

R is _absent or is hydrogen or an alkyl, alkoxy, amino, nitro, hydroxy, halogen, trifluoromethyl, cyano, alkenyl or alkynyl group, preferably hydrogen if _present ;

And where dashed lines indicate that single or double bonds may be present.

In specific embodiments, the steroid is one or more of a series of sedative-hypnotic 3 alpha-hydroxy ring A-reduced pregnanesteroids, including sedative-hypnotic 3 alpha-hydroxy ring A-reduced pregnanesteroids, which include The main metabolites of ketone and deoxycorticosterone are 3α-hydroxy-5α-pregnane-20-one (isopregnanolone) and 3α,21-dihydroxy-5α-pregnane-20-one (isopregnanolone) Tetrahydro DOC (allotetrahydroDOC)). These 3α-hydroxysteroids do not interact with classical intracellular steroid receptors, but instead bind stereoselectively and with high affinity to the major inhibitory neurotransmitter gamma-amino-butyric acid (GABA) in the brain on the receptor.

In certain embodiments, the neuroactive steroid is progesterone, isopregnalone, or other progesterone analogs. In a specific embodiment, the neuroactive steroid is isopregnalone or a derivative thereof. Exemplary derivatives include, but are not limited to, (20R)-17β-(1-hydroxy-2,3-butadienyl)-5α-androstane-3α-ol (HBAO). Additional derivatives are described in WO 2012/127176.

The lipophilicity of isopregnalone can make it unique when formulated for in vivo administration. As noted above, isopregnalone can be formulated with a base, such as cyclodextrin, to improve solubility. Alternatively or additionally, isopregnalones may be modified in an attempt to increase solubility. For example, a polar group can be introduced at position 16α with the aim of increasing water solubility, brain accessibility and potency of neuroactive steroids, as described in Kasal et al., J.Med.Chem., 52(7), 2119- 215 (2009).

As used herein, "neuroactive steroid" also includes pharmaceutically acceptable, pharmacologically effective derivatives of neuroactive steroids, including individual neuroactive steroid enantiomers (dextro- and levo-enantiomers) and their pharmaceutical Unless otherwise specified, the neuroactive steroid enantiomeric mixtures and their pharmaceutically acceptable salts, and the active metabolites of neuroactive steroids and their pharmaceutically acceptable salts. It will be appreciated that in some cases it may be necessary to adjust the dosage of enantiomers, derivatives and metabolites according to the relative activity of the racemic mixture of neuroactive steroids.

As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid addition or base addition salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those obtained from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and from organic acids such as acetic, propionic, succinic, glycolic, hard Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfamic acid, 2-acetyl Salts prepared from oxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionate.

Pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, the preparation of these salts may involve reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704.

As used herein, the phrase "pharmaceutically acceptable" means that these compounds, substances, compositions and/or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, Anaphylaxis, or other problems, or complications commensurate with a reasonable benefit/risk ratio.

Neuroprotective steroids generally contain one or more chiral centers and therefore exist as one or more stereoisomers. Such stereoisomers can be prepared and/or isolated as individual enantiomers, diastereomeric mixtures or racemic mixtures.

As used herein, the term "stereoisomer" refers to a compound composed of the same atoms having the same sequence of bonds but a different three-dimensional arrangement of the atoms which are not interchangeable. The three-dimensional arrangement is called a configuration. The term "enantiomer" as used herein refers to two stereoisomers which are nonsuperimposable mirror images of each other. The term "optical isomer" as used herein is equivalent to the term "enantiomer". As used herein, the term "diastereomers" refers to two stereoisomers that are not mirror images and are also nonsuperimposable. The terms "racemate", "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are attached. Selection of appropriate chiral columns, eluents and conditions necessary to achieve separation of enantiomeric pairs is well known to those skilled in the art using standard techniques (see e.g. Jacques, J. et al., "Enantiomers, Racemates, and Resolutions ", John Wiley and Sons, Inc., 1981).

B. Dosage and Pharmacokinetics

Compositions comprising therapeutically effective concentrations of progesterone, isopregnalone, or synthetic progestins can be administered using any acceptable method known in the art. For example, a pharmaceutical composition comprising progesterone, isopregnalone, or a synthetic progestin may be administered by any method, including intramuscular (IM) injection, subcutaneous (SC) injection, intrathecal, or via the lungs, nose, or mucosa. drug route) to administer the drug. Formulations are designed to mimic intra-CNS levels achieved with progesterone, isopregnolone, or synthetic progestins that The administration of is by infusion over about 1 to about 120 hours, more preferably over about 24 to about 72 hours, over about 48 to about 96 hours, or over about 24 to about 120 hours.

In one embodiment, the dose of progesterone, isopregnanolone or synthetic progestin is equivalent to about 0.1 ng to about 100 g/kg body weight, about 10 ng to about 50 g/kg body weight, about 100 ng to about 1 g/kg of body weight, about 1 μg to about 100 mg/kg of body weight, about 1 μg to about 50 mg/kg of body weight, about 1 mg to about 500 mg/kg of body weight, and about 1 mg to about 50 mg/kg of body weight Parenteral administration. Additionally, administration of the progesterone, isopregnalone, or synthetic progestogens achieves a therapeutically effective dose in an amount of about 0.1 ng, 1 ng, 10 ng, 100 ng, 1 μg, 10 μg, 100 μg, 1 mg, 1.5 mg, 2 mg, 3 mg . , 500 mg (based on body weight per kg) or greater. Although progesterone, isopregnanolone, or synthetic progestins may be administered once or several times a day, and the duration of treatment may be once daily for about 1, 2, 3, 4, 5, 6, 7 days or more; but More preferred administration is a single dose in the form of a single dosage unit or several smaller dosage units, or multiple administrations by subdividing the dose at regular intervals. For example, dosage units can be administered from about 0 hours to about 1 hour, from about 1 hour to about 24 hours, from about 1 to about 72 hours, from about 1 to about 120 hours, or from about 24 hours to at least about 120 hours after injury. Alternatively, the dosage unit may be administered at about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 30, 40, 48, 72, 96, 120 hours or longer. Administration of subsequent dosage units after the initial administration may be at any time such that a therapeutic effect is achieved. For example, administration of increasing dosage units can protect a subject from secondary episodes of edema, which may occur within days of the first injury. Therapy with progesterone, isopregnolone, or synthetic progestogens can be changed to a multistage dosing regimen that includes progesterone, isopregnolone, or synthetic progestins The hormone is administered over two or more time periods, preferably for a combined period of about 12 hours to about 7 days, including, 1, 2, 3, 4 or 5 days or about 15, 15, 30, 35, 40 , 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140 or 144 hours or about 1 to 24 hours, About 12 to 36 hours, about 24 to 48 hours, about 36 to 60 hours, about 48 to 72 hours, about 60 to 96 hours, about 72 to 108 hours, about 96 to 120 hours or about 108 to 136 hours. In one embodiment, the combined duration of the two-stage dosing regimen of progesterone, isopregnolone, or synthetic progestin is from about 1 day to about 5 days; The combined duration of the two-stage dosing regimen of the synthetic progestins is from about 1 day to about 3 days. In one embodiment, the progesterone, isopregnolone, or synthetic progestin (which will be administered during the first and second time periods of the two-stage dosing regimen of the progesterone, isopregnolone, or synthetic progestin) administration) is selected so that the higher total hourly dose of progesterone, isopregnolone, or synthetic progestin is given in the first time period while the higher total hourly dose of progesterone, isopregnolone, or synthetic progestin The lower hourly dose of progestin is given in the second time period. The first and second time periods of the two-stage dosing regimen of progesterone, isopregnalone, or synthetic progestin may vary for an individual depending on the individual's health and history of traumatic injury. Typically, subjects with a higher total daily dose of progesterone, isopregnolone, or synthetic progestin in a two-stage dosing regimen of 1 to 5 days of progesterone, isopregnolone, or synthetic progestin The hourly dosing duration is at least 1, 2, 3, 4, 5, 6, 12 or 24 hours. The length of the second period of time can be adjusted accordingly and ranges, for example, from about 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, or from about 12 to about 36 hours. hours, about 24 to about 36 hours, about 24 to about 48 hours, about 36 hours to about 60 hours, about 48 hours to about 72 hours, about 60 hours to about 84 hours, about 72 hours to about 96 hours or about 108 hours to about 120 hours. Thus, for example, when a two-stage dosing regimen of progesterone, isopregnolone, or synthetic progestin is combined over 3 days, the higher total dose of progesterone, isopregnolone, or synthetic progestin may be Dosing occurs within the first hour, and the duration of administration of the lower total hourly dose of progesterone, isopregnalone, or synthetic progestin can range from 2 to 72 hours.

The area under the curve (AUC) refers to the curve (which records the concentration of progesterone, isopregnolone, or synthetic progestin after IV administration of a reference progesterone, isopregnolone, or synthetic progestin standard). Area under serum concentration (nmol/L) at a given time. For "reference progesterone, isopregnolone, or synthetic progestin standard" means the total hourly dose used to determine the progesterone, isopregnolone, or synthetic progestin to be administered to patients with trauma In order to obtain the desired positive effect, that is, a positive therapeutic response (the positive effect, that is, a positive therapeutic response, in the absence of administration of progesterone, isopregnalone, or synthetic progestogens) As observed below, are improved)) baseline progesterone, isopregnolone, or synthetic progestogen formulations. In one embodiment, the dose of progesterone, isopregnolone or synthetic progestin to be administered ensures a final serum level of progesterone, isopregnolone or synthetic progestin of from about 100 ng/ml to about 1000ng/ml, about 1100ng/ml to about 1450ng/ml, 100ng/ml to about 250ng/ml, about 200ng/ml to about 350ng/ml, about 300ng/ml to about 450ng/ml, about 350ng/ml to about 450ng/ml /ml, about 400ng/ml to about 550ng/ml, about 500ng/ml to about 650ng/ml, about 600ng/ml to about 750ng/ml, about 700ng/ml to about 850ng/ml, about 800ng/ml to about 950ng/ml /ml, about 900ng/ml to about 1050ng/ml, about 1000ng/ml to about 1150ng/ml, about 100ng/ml to about 1250ng/ml, about 1200ng/ml to about 1350ng/ml, about 1300ng/ml to about 1500ng/ml /m. In specific embodiments, the serum level of progesterone, isopregnalone, or synthetic progestin is about 100 ng/ml, 250 ng/ml, 300 ng/ml, 350 ng/ml, 360 ng/ml, 370 ng/ml, 380 ng/ml , 390ng/ml, 400ng/ml, 410ng/ml, 420ng/ml, 430ng/ml, 440ng/ml, 450ng/ml, 500ng/ml, 750ng/ml, 900ng/ml, 1200ng/ml, 1400ng/ml or 1600ng /ml. In other embodiments, the constant progesterone, isopregnolone, or synthetic progestin therapy or the bi-level progesterone, isopregnolone, or synthetic progestin therapy includes a final period during which the progesterone, The administration of isopregnalone or synthetic progestins is tapered. By "tapering dosing" it is meant a dosing regimen that reduces the dose administered to the patient and thus produces a gradual decrease and eventual elimination of progesterone, isopregnalone or synthetic progestogen, It is either for a fixed period of time, or the period depends on the empirical judgment of the physician based on routine monitoring of the subject's response to treatment for traumatic central nervous system injury. The period of tapering progesterone, isopregnalone or synthetic progestin administration may be about 12, 24, 36, 48 hours or longer. Alternatively, the timing of the tapering progesterone, isopregnalone, or synthetic progestin administration may range from about 1 to 12 hours, from about 12 to about 48 hours, or from about 24 to about 36 hours. Tapering of the drug used may be a "linear" taper. For example, a "10%" linear taper off run from 500 mg could be 500, 450, 400, 350, 300, 250, 200, 150, 100, 50. Alternatively, an exponential taper could be used, which would be, for example, 500, 450, 405, 365, 329, 296, 266, 239, etc. if the procedure outlined above is used as an example. Thus, a linear or exponential taper of about 5%, 10%, 20%, 30% or 40% can be used in the methods of the invention. Additionally, about 1% to 5%, about 6% to 10%, about 11% to 15%, about 16% to 20%, about 21% to 25%, about 26% to 30%, about 31% to 35%, about 36% to 40% linear or exponential taper off.

When a treated subject, after completing the first cycle of therapy, shows a partial response or relapses, subsequent courses of progesterone, isopregnolone, or synthetic progestin therapy are required to achieve partial or complete response. treatment response. Therefore, at the time of first treatment (which may include a constant progesterone, isopregnolone, or synthetic progestogen dosing regimen or a two-stage dosing regimen of progesterone, isopregnolone, or synthetic progestin) Following an idle period, the subject may receive one or more additional treatment sessions comprising a constant or bi-level progesterone, isopregnalone, or synthetic progestogen dosing regimen. Such periods of idle time between treatment times are referred to herein as discrete periods of time. It is believed that the length of the discrete time periods will depend on the degree of response (ie full versus partial) the subject has obtained with any prior treatment period of progesterone, isopregnolone or synthetic progestin therapy. These multiple treatment courses are referred to herein as maintenance cycles, where each maintenance cycle includes a completely constant or bi-level dosing regimen of progesterone, isopregnolone, or synthetic progestin. For "a complete two-stage dosing regimen of a progesterone, isopregnolone, or synthetic progestin" it means the first period and the second period of administration of the progesterone, isopregnolone, or synthetic progestin Both segments have been administered to subjects. The need for multiple maintenance cycles can be assessed by monitoring the patient for physical and behavioral improvement. The time between maintenance periods can be about 1 hour, 15 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or other such that falls within the range of about 1 day to about 14 days period.

As used herein, "about" means approximately plus or minus ten percent.

C. Preparations

Neuroactive steroid formulations contain one or more neuroactive steroids in combination with one or more pharmaceutically acceptable excipients. In some cases, the formulation contains a neuroactive steroid. In other cases, the formulation includes a mixture of two or more neuroactive steroids. Neuroactive steroids may be incorporated in the formulations described below as neutral compounds, pharmaceutically acceptable salts and/or prodrugs or metabolites.

Pharmaceutical formulations may be designed for immediate, sustained, delayed and/or burst release of one or more neuroactive steroids in a therapeutically effective amount. In one embodiment, the formulation provides an initial burst of "loading dose" followed by sustained release to maintain a therapeutically effective dose. This can be accomplished through the use of delayed and/or extended release formulations.

1. Solubilization of neuroactive steroids

Many neuroactive steroids have limited water solubility. To ensure formulations capable of delivering therapeutically effective doses, various approaches can be used to enhance the solubility and biocompatibility of neuroactive steroids. See, eg, "Water-Insoluble Drug Formulation", 2nd Edition, edited by Rong Liu (CRC Press, Boca Raton, FL, 2008). Solubilized formulations of one or more neuroactive steroids can be prepared using the techniques described below. These solubilized formulations can be further incorporated into parenteral and non-parenteral formulations described in Sections 2 and 3

a. Inclusions

Neuroactive steroid solubility can be improved by encapsulation (ie host-guest formulation). When a non-polar molecule (i.e., a guest, such as a drug with poor water stability) or part of a molecule inserts into the non-polar cavity of another molecule or group of molecules (i.e., the host), Then an envelope is formed. If the singular host molecule or the plurality of host molecules exhibit good aqueous solubility, the solubility of the host-host complex is greater than that of the individual host.

Complexes containing or comprising one or more neuroactive steroids can be formed using all suitable host molecules or molecules. For example, the aqueous solubility of neuroactive steroids can be increased by encapsulation with cyclodextrins. Steroid-cyclodextrin complexes are known in the art. See, eg, US Patent 7,569,557 by Backensfeld et al. and US Patent Application Publication US 2006/0058262 by Zoppetti et al.

Glucans are soluble polysaccharides produced by bacteria and yeast. They are characterized by a predominant (>95%) α(1-6) backbone linkage and usually at branch points 1, 2 in varying proportions of α(1-2), α(1-3) and α( 1-4) keys. Dextrins are partially hydrolyzed homopolymers of glucose composed entirely of α(1-4) backbone linkages.

Cyclodextrins are glucose residues that contain or include six (α-cyclodextrin), seven (β-cyclodextrin), eight (γ-cyclodextrin) or higher α-(1,4)-linkages of cyclic oligosaccharides. The hydroxyl groups of the cyclodextrins are oriented towards the outside of the ring while the glycosidic oxygen and non-exchangeable hydrogen atoms of the two rings are oriented towards the inside of the cavity. As a result, cyclodextrins possess a hydrophobic interior cavity combined with a hydrophilic exterior that imparts water solubility. When combined with a hydrophobic drug such as a neuroactive steroid, the neuroactive steroid (ie, the guest) inserts into the hydrophobic interior of the cyclodextrin (ie, the host). The host-host-guest complexes retain water solubility as a result of the hydrophobic exterior of the cyclodextrin ring.

The neuroactive steroid-cyclodextrin complex, when solubility permits, can be incorporated into any of the parenteral and non-parenteral formulations described below. If desired, the aqueous solubility of the solid neuroactive steroid-cyclodextrin complex can be isolated by lyophilization as a solid neuroactive steroid-cyclodextrin complex (by freeze-drying) and/or by micronizing the solid neuroactive steroid-cyclodextrin complex. Dextrin complex for further enhancement.

This ring-like orientation provides a truncated cone structure that is hydrophilic on the outside and lipophilic on the inside. Cyclodextrin complexes are formed when host molecules are partially or completely contained inside the chamber. The parent α-, β- and γ-cyclodextrins (especially β) have limited aqueous solubility and exhibit toxicity when administered parenterally. Thus, the parent cyclodextrin structure can be chemically modified to produce parenterally safe CD derivatives. The modification is typically at one or more of the 2, 3 or 6 hydroxyl groups.

The neuroactive steroid-cyclodextrin complex is preferably formed from a cyclodextrin selected from alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin and derivatives thereof. Cyclodextrins can be chemically modified to allow some or all of the macrocycle's primary or secondary hydroxyl groups, or both, to be functionalized with pendant groups. Suitable pendant groups include, but are not limited to, sulfinyl, sulfonyl, phosphate, acyl, and C ₁ -C ₁₂ alkyl groups (optionally substituted with one or more (e.g., 1, 2, 3 or 4) hydroxyl, carboxyl, carbonyl, acyl, oxy, oxo), or combinations thereof. Methods of modifying these alcohol residues are known in the art, and many cyclodextrin derivatives are commercially available, including the sulfobutyl ether β-cyclodextrin which is available under the trademark Obtained from Ligand Pharmaceuticals (La Jolla, CA).

Examples of suitable cyclodextrins for use in the formulation of neuroactive steroids, such as isopregnalone, may include the cyclodextrins disclosed in US Patent Nos. 5,874,418; 6,046,177; and 7,635,733, which are incorporated herein by reference. Other examples of suitable cyclodextrins for neuroactive steroid formulations include non-exhaustively alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, methyl alpha-cyclodextrin, methyl beta - Cyclodextrin, Methyl γ-cyclodextrin, Ethyl β-cyclodextrin, Butyl α-cyclodextrin, Butyl β-cyclodextrin, Butyl γ-cyclodextrin, Amyl γ-cyclodextrin Dextrin, Hydroxyethyl β-cyclodextrin, Hydroxyethyl γ-cyclodextrin, 2-Hydroxypropyl α-cyclodextrin, 2-Hydroxypropyl β-cyclodextrin, 2-Hydroxypropyl γ- Cyclodextrin, 2-Hydroxybutyl β-cyclodextrin, Acetyl α-cyclodextrin, Acetyl β-cyclodextrin, Acetyl γ-cyclodextrin, Propionyl β-cyclodextrin, Butyryl β - Cyclodextrin, Succinyl α-Cyclodextrin, Succinyl β-Cyclodextrin, Succinyl γ-Cyclodextrin, Benzoyl β-Cyclodextrin, Palmyl β-Cyclodextrin, Toluene Sulfonyl β-cyclodextrin, Acetylmethyl β-cyclodextrin, Acetylbutyl β-cyclodextrin, Glucosyl α-cyclodextrin, Glucosyl β-cyclodextrin, Glucosyl γ -Cyclodextrin, Maltosyl α-Cyclodextrin, Maltosyl β-Cyclodextrin, Maltosyl γ-Cyclodextrin, α-Cyclodextrin Carboxymethyl Ether, β-Cyclodextrin Carboxymethyl Ether, γ -Cyclodextrin Carboxymethyl Ether, Carboxymethylethyl β-Cyclodextrin, Phosphate α-Cyclodextrin, Phosphate β-Cyclodextrin, Phosphate γ-Cyclodextrin, 3-Trimethylammonium -2-Hydroxypropyl β-cyclodextrin, Sulfobutyl ether β-cyclodextrin, Carboxymethyl α-cyclodextrin, Carboxymethyl β-cyclodextrin, Carboxymethyl γ-cyclodextrin, and their combinations.

Preferred cyclodextrins include, but are not limited to, alkyl cyclodextrins, hydroxyalkyl cyclodextrins such as hydroxypropyl beta-cyclodextrins, carboxyalkyl cyclodextrins and sulfoalkyl ether cyclodextrins such as Sulfobutyl ether beta-cyclodextrin.

In specific embodiments, the cyclodextrin is an alpha, beta, or gamma cyclodextrin, which has a plurality of charges (eg, negative or positive) on the surface. In a more specific embodiment, the cyclodextrin is a beta-cyclodextrin that contains or includes a plurality of functional groups that are negatively charged at physiological pH. Examples of such functional groups include, but are not limited to, carboxylic acid (carboxylate) groups, sulfonate (RSO ₃ ⁻ ), phosphonate, phosphinate, and amino acids, which are negatively charged at physiological pH. These charged functional groups can be directly bonded to the cyclodextrin or can be bonded through a spacer such as an alkylene chain. The number of carbon atoms in the alkylene chain can vary, but will generally be from about 1 to 10 carbons, preferably 1-6 carbons, more preferably 1-4 carbons. Highly sulfated cyclodextrins are described in US Patent 6,316,613.

In one embodiment, the cyclodextrin is a β-cyclodextrin functionalized with multiple sulfobutyl ether groups. Such cyclodextrins are sold under the trade name to sell.

is a polyanionic β-cyclodextrin derivative with the sodium salt of sulfonate separated from the lipophilic compartment by a butyl ether spacer or sulfobutyl ether (SBE). Not a single chemical substance, but a structure composed of multiple polymers of varying degrees of substitution and positional/regioisomers, produced by a patented manufacturing process relentlessly practiced and refined to control impurities Instructions and controls into a uniform structure.

Each cyclodextrin molecule contains six to seven sulfobutyl ether groups. Because of the very low pKa of the sulfonic acid group, the Carries multiple negative charges at physiologically compatible pH. The four-carbon butyl chain plus the repulsion of the negative charge of the end group "extends" the cyclodextrin cavity. This often results in stronger binding to the drug candidate than can be achieved with other modified cyclodextrins. It also offers the potential for ionic-charge interactions between cyclodextrins and positively charged drug molecules. In addition, these derivatives confer excellent solubility and parenteral safety on the molecule. Compared to β-cyclodextrin, Provides higher interaction profile and excellent water solubility (more than 100 g/100ml, 50 times improvement).

In other embodiments, the cyclodextrin has functional groups that are negatively charged at physiological pH. Suitable positively charged groups include, but are not limited to, quaternary ammonium groups. Exemplary cyclodextrins include, but are not limited to, mono-6(A)-butylammonium-6(A)-deoxy-β-cyclodextrin tosylate (BuAM-β-CD) and amine- and guanidine- Derivatized β-cyclodextrin (βCD).

Preferably, the cyclodextrin is present in an amount of about 0.1% to about 40% w/w of the overall formulation, preferably about 5% to about 40% w/w, more preferably about 10% to about 40% w/w, most preferably From about 10% to about 35% w/w. In certain embodiments, the concentration of cyclodextrin is from about 15% to about 35% w/w, preferably from about 20% to about 35% w/w, more preferably from about 30% to about 35% w/w. In one embodiment, the formulation contains from about 1 to about 2, preferably about 1.5 mg of a neuroactive steroid (eg, isopregnalone) per ml of cyclodextrin such as count.

b. Ion exchange resin

Ion exchange resins (IERs) are high molecular weight water-insoluble polymers that contain or include fixed positively or negatively charged functional groups in their matrix that have an affinity for oppositely charged counterions. IERs are insoluble high molecular weight solid polyelectrolytes capable of reversible and stoichiometric exchange with the surrounding medium. IER is a styrene (divinylbenzene) copolymer containing or comprising - acidic groups: carboxyl or sulfo for cationic E.R, - basic groups: quaternary ammonium for anionic E.R

IE processes are known for cation exchange (CE) or anion exchange (AE) based on the nature of the ionic species exchanged. The IE process is inherently competitive. In practice, the drug in ionic form (usually in solution) is mixed with the appropriate IER form complex (known as "resinate").

The performance of resinates is governed by several factors such as:

1. The pH and temperature of the drug solution;

2. Molecular weight and charge strength of drug and IER;

3. Geometry;

4. Mixing speed;

5. The ionic strength of the drug solution;

6. The degree of cross-linking and particle size of IER;

7. The nature of the solvent; and

8. Contact time between drug substance and IER.

Generally, the IER is composed of spherical beads approximately 0.5–1.2 mm in diameter. The most commonly used type is opaque yellow in color, although other colors have also been reported. The structure of the respective spherical particles of the IER is similar to that of a homogeneous gel. The contraction or expansion of the spherical volume occurs based on the ionic environment present in the IER.

The main disadvantage of controlled or sustained-release systems is dose dumping, posing an increased risk of toxicity. Ion exchange resins provide better drug retention and prevent dose dumping. The polymeric (physical) and ionic (chemical) properties of ion exchange resins result in a more uniform drug release than a simple matrix (due to physical properties alone). Strong IER resinate loaded drug provides a simple form of controlled or sustained release delivery system. The resinate can be directly filled in a capsule, suspended in a liquid, suspended in a matrix or compressed into a tablet. The drug will be slowly released and absorbed by the ion exchange phenomenon.

Microencapsulation of resinates provides better control over drug release (oral release or prolonged release). Absorption of drug from the coating resinate is a result of counterion entry into the coating resinate and release of drug ions from the drug resin complex by ion exchange methods and diffusion of drug ions through the membrane into the dissolution medium. The designed release rate at the desired level can be obtained by optimizing the coating thickness. Microencapsulation of resinates can be achieved by air suspension coating (Wurster process), interfacial polymerization, solvent evaporation or pan coating.

Modification of resinate coatings, eg by pre-treatment with polyethylene glycol 400, can be used to preserve geometry and improve coating process. The pretreated resinate is then coated with ethyl cellulose or any other water insoluble polymer. Polyethylene glycol helps control the matrix's swelling rate in water, while an external ethylcellulose coating improves the diffusion pattern of ions into and out of the system. The main disadvantage of controlled or sustained-release systems is dose dumping, posing an increased risk of toxicity. Ion exchange resins provide better drug retention and prevent dose dumping. The polymeric (physical) and ionic (chemical) properties of ion exchange resins allow for more uniform drug release compared to simple matrices.

Strong IER resinate loaded drug provides a simple form of controlled or sustained release delivery system. The resinate can be directly filled in a capsule, suspended in a liquid, suspended in a matrix or compressed into a tablet. The drug will be slowly released and absorbed by the ion exchange phenomenon.

There are some ion exchange resins suitable for intravenous administration of drugs. For example, Shimada, et al., in Jpn J. Antibiot. 1985 Sep; 38(9):2496-502, describe clinical studies on unmodified intravenous dry ion exchange resin treated human normal immunoglobulins. In studies, SM-4300 showed efficacy with no apparent fever-reducing effect, opsonizing effect, or healing of lesions.

c. Lipid carrier

To facilitate the administration of poorly water soluble neuroactive steroids, various lipid carriers are available.

lipid emulsion

Neuroactive steroids can be suspended or dissolved combinatorially through the use of lipid emulsions. Lipid emulsions are known in the art. See, eg, US Patent 6,361,792 to Long et al; US Patent 7,550,155 to Zhang et al; and US Patent Application Publication US 2006/0067952. Lipid emulsion formulations typically include one or more neuroactive steroids, an oil component, an emulsifier and water.

The oil component can be monoglycerides, diglycerides, triglycerides or combinations thereof. In some cases, the oil component includes esters formed between one or more fatty acids and alcohols other than glycerol. The oil component may be, for example, a vegetable oil such as almond oil, borage seed oil, blackcurrant seed oil, corn oil, safflower oil, soybean oil, sesame oil, cottonseed oil, peanut oil, olive oil, rapeseed oil, coconut oil, Palm oil, canola oil or combinations thereof. Vegetable oils are generally long-chain triglycerides formed from C ₁₄ -C ₂₂ fatty acids. The oil component may also include medium chain triglycerides formed from C8-C12 fatty acids, such as Miglyol 812, GTCC-PN or Neobees M-5 oil.

Emulsifiers are used to stabilize lipid emulsions by preventing the separation of the emulsion into separate oil and water phases. Suitable emulsifiers include, but are not limited to, propylene glycol mono- and di-fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypropylene co-polymers and Block co-polymers, salts of fatty alcohol sulfates, sorbitan fatty acid esters, esters of macrogol glyceryl ethers, oil and wax type emulsifiers, glyceryl monostearate, glyceryl sorbitan Fatty acid esters and phospholipids. In some cases the emulsifier is a phospholipid.

In some instances, the emulsifier is a vitamin E derivative. Suitable vitamin E derivatives include, but are not limited to, alpha-tocopheryl oxalate, alpha-tocopheryl malonate, alpha-tocopheryl succinate, alpha-tocopheryl glutarate, alpha-tocopheryl Adipate, Alpha Tocopheryl Pimelate, Alpha Tocopheryl Suberate, Alpha Tocopheryl Azelate and D-Alpha Tocopheryl Macrogol 1000 Succinate (Vitamin ETPGS) .

Exemplary phospholipids include, phosphatidyl chloride, lecithin (a mixture of choline esters of phosphorylated diacylglycerides), phosphatidylethanolamine, phosphatidylglycerol, having from about 4 to about 22 carbon atoms and more typically about 10 Phosphatidic acids of up to about 18 carbon atoms and varying degrees of saturation. Preferably, the phospholipids are of natural origin. Naturally occurring phospholipids include soy lecithin, egg lecithin, hydrogenated soy lecithin, hydrogenated egg lecithin, sphingosines, gangliosides, and phytosphingosines, and combinations thereof.

Suitable lipid emulsions typically contain about 1% to 40% w/v oil component and about 0.1% to 7.5% w/v emulsifier. Suitable commercially available lipid emulsions include lipid emulsions containing or comprising soybean oil, such as 10%, 20% and 30%, and the included lipid emulsions contain or include soybean and safflower oils, such as II10% and II 20% mixture.

The lipid emulsion may optionally contain one or more additional components. For example, lipid formulations may contain one or more anhydrous miscible co-solvents, such as alcohols or glycols. In some preferred formulations, glycerol and/or propylene glycol are present as co-solvents.

Many lipid emulsions are capable of supporting bacterial growth. Thus, in some cases, one or more components, such as disodium edetate, citric acid, metasulfite, benzyl alcohol, one or more para-hydroxybenzoates, chlorobutanol, phenol, sorbic acid, or thimerosal.

In addition, lipid emulsions may contain one or more agents for changing or stabilizing the pH of the solution, including phosphate buffers, acetate buffers and citrate buffers.

In one embodiment, the formulation is an oil-in-water emulsion containing or comprising a therapeutically effective amount of one or more neuroactive steroids dissolved in a solution comprising or comprising about 1% w/ v to about 25% w/v soybean oil, about 0.5% to about 7.5% w/v egg yolk phospholipid, and about 0.5% w/v to about 5% w/v miscible co-solvent.

In another embodiment, the formulation is an oil-in-water emulsion containing or comprising a therapeutically effective amount of one or more neuroactive steroids dissolved in a solution comprising or comprising about 1% w /v to about 15% w/v soybean oil, about 1% w/v to about 15% w/v safflower oil, about 0.5% to about 7.5% w/v egg phospholipids, and 0.5% w/v to about 5% w/v of miscible co-solvents.

Lipid emulsions can be administered as described above, or incorporated into parenteral formulations as described below.

Liposomes

One or more neuroactive steroids can be incorporated into the liposomes. Liposomes are generally obtained from phospholipids or other lipid substances, as known in the art. See, e.g., "Remington-The science and practice of pharmacy", 20th ed., Jennaro et al. (Phila, Lippencott, Williams, and Wilkens, 2000).

Liposomes are generally obtained from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. Compositions of the present disclosure in liposome form can contain, in addition to one or more neuroactive steroids, stabilizers, preservatives, excipients and other suitable excipients.

Examples of suitable lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See, e.g., Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York p. 33 etseq., 1976 Liposomes can be cationic liposomes (e.g., based on DOTMA, DOPE, DC cholesterol) or anionic lipids body. Liposomes can further include proteins, if desired, to facilitate targeting to specific cells. Administration of a composition comprising a compound and cationic liposomes can be administered to the blood for transfusion into a target organ or inhaled into the respiratory tract to target cells of the respiratory tract.

One or more neuroactive steroids can be formulated using commercially available liposomal formulations such as (GIBCO-BRL, Inc., Gaithersburg, Md.), (Qiagen, Inc. Hilden, Germany) and (PromegaBiotec, Inc., Madison, Wis.), and other liposomes developed according to state-of-the-art process standards. Diffusion of the compound in liposomes or delivery of the compound in liposomes designed for a specific rate or dose can also be used.

One or more neuroactive steroids can also be formulated using vesicles. Vesicles are multilamellar or unilamellar vesicles that include nonionic surfactants. Aqueous solutions of solutes are encapsulated by bilayers resulting from the assembly of surfactant macromolecules. Similar to liposomes, vesicles are also used for targeted delivery of, for example, anticancer drugs including methotrexate, doxorubicin, and immune adjuvants. They are generally considered to be distinct from delivery plastids (vesicles made from amphiphilic carbohydrates and polymers such as chitosan containing or including amino groups).

One or more neuroactive steroids can also be delivered using nanoerythrosomes. Nanoerythrosomes are nanovesicles made from red blood cells by dialysis (through a filter with defined pore size). These vesicles can be loaded with one or more neuroactive steroids.

lipid nanoemulsion

Lipid nanoemulsions can also be used. Lipid nanoemulsions are known in the prior art. See, eg, US Patent Application Publication US 2007/0207173 by Chen et al. and US Patent Application Publication US 2001/0045050 by Elbayoumi et al. Lipid nanoemulsions can be prepared by microemulsifying any of the above-mentioned lipid emulsions by using, for example, a high-pressure homogenizer or via a phase inversion temperature method (PIT).

In preferred lipid nanoemulsions containing or including neuroactive steroids, vitamin E succinate and/or vitamin ETPGS are included as emulsifiers.

Lipid nanoemulsions can be further lyophilized if desired. See, eg, U.S. Patent Publication US 2011/0015266.

Lipid nanoemulsions can be administered as described above, or incorporated into parenteral or non-parenteral formulations as described below.

The oily phase comprised by the preconcentrate has at least one fatty acid oil. The fatty acid oils of the present invention include at least one polyunsaturated fatty acid. The term "polyunsaturated fatty acid" includes those fatty acids having at least 50% by weight polyunsaturated fatty acid or higher. Polyunsaturated fats can be found in cereal products, fish and seafood (herring, salmon, mackerel, star flounder), soybeans and fish oils. Polyunsaturated fatty acids include omega-3 fatty acids and omega-6 fatty acids. Polyunsaturated fatty acids include linoleic acid and linolenic acid. Preferred polyunsaturated fatty acids include eicosapentaenoic acid, salts of eicosapentaenoic acid, docosahexaenoic acid, salts of docosahexaenoic acid, triglycerides of eicosapentaenoic acid esters, triglyceride of docosahexaenoic acid, ethyl ester of eicosapentaenoic acid or ethyl ester of docosahexaenoic acid.

Polyunsaturated fatty acids include omega-3 fatty acid oils and medium chain triglycerides (MCTs). Medium chain triglycerides containing about 6 to 14 carbon atoms, preferably about 8 to 12 carbon atoms, are suitable for use in the oil phase. Preferred medium-chain glycerides include, for example, caprylic/capric triglycerides such as "Migriol 810", "Migriol 812" (both are trade names, manufactured by Huls Co., Ltd., available from Mitsuba Trading Co. , Ltd.), glyceryl tricaprylate (tricapryl) such as "Panasate 800" (trade name, manufactured by NOF Corporation, Japan).

The pre-concentrate includes an emulsifier component. The emulsifier component has one or more surfactants. Surfactants include any molecule that has both a polar head group (which actively prefers solvation by water) and a hydrophobic tail (which is not well solvated by water). The ratio of oil phase to emulsifier components is important with regard to the toxicity of the nanoemulsions prepared from this preconcentrate. Surfactants suitable for use in preconcentrates and emulsions include various anionic and nonionic surfactants, and other emulsifying compounds that facilitate the formation of oil-in-water emulsions; provided they are on the GRAS (Generally Regarded as Safe) list and Anything approved for human consumption will do, such as lecithin, solutol HS-15 (polyoxyethylene ester of 12-hydroxystearate), polysorbate 80, or Cremophore EL (polyethoxylated castor oil). See McCutcheon's Volume 1: Emulsifiers and Detergents North American Edition, 1996 (incorporated herein by reference).

2. Preparations for parenteral administration

The compounds described herein can be formulated for parenteral administration. As used herein, "parenteral administration" means intravenous or intraarterial administration.

particle size reduction

The solubility of one or more neuroactive steroids can be improved by reducing the particle size of the drug. By reducing the particle size, the surface area to volume ratio of the drug particle is increased, resulting in increased solvation of the drug particle.

Particle size reduction can be achieved using various micronization techniques including, but not limited to, grinding, milling (e.g., gas-milling (jet milling), ball milling), agglomeration, high pressure homogenization, spray drying, and/or Supercritical fluid crystallization. In some cases, the particles undergo size changes by mechanical impact (eg, by hammer mills, ball mills, and/or pin mills). In some cases, the particles undergo a size change with the aid of fluid energy (eg, by a spiral jet mill, an annular jet mill, and/or a fluidized bed jet mill). After micronization, the drug particles can be further processed. For example, micronized drug particles can be coated to further affect solubility and/or drug release.

Micronized drug particles can be crystalline or amorphous depending on the micronization process and the associated active agent. Using micronization technology, it is possible to form drug particles from 10nm to 100 microns. The average particle size and distribution of drug particles can be controlled by choice of micronization technique and by changing process conditions. Accordingly, drug particle formulations containing drug nanoparticles, drug microparticles, and combinations thereof can be prepared. Appropriate micronization techniques can be chosen to produce drug particle populations with monodisperse or polydisperse particle size distributions. Methods of producing monodisperse drug particles are known in the art. In addition, the population of drug particles can be separated after micronization, so that the obtained population of drug particles has the desired size range and distribution.

In addition to enhancing solubility, micronization can also be used to control drug release profiles. Because drug particles of different sizes dissolve at different rates and over different periods of time, micronization can be used to prepare controlled-release, sustained-release, pulsatile-release, and delayed-release formulations. For example, populations of micronized drug particles having different average particle sizes and/or different particle size distributions can be mixed. The resulting mixture exhibits a combination of drug release profiles that will be those of the constituent populations of the drug particles. In some embodiments, micronized drug particles containing or including different neuroactive steroids may be mixed for combination therapy.

Micronized drug particles can be incorporated into any of parenteral and non-parenteral formulations (described below as suspensions or dispersions in solid or fluid carriers). Micronized drug particles can also be used to form solutions for parenteral or non-parenteral administration. Micronized drug particles may also be provided, for example, as a kit for injection for the preparation of solutions or suspensions.

water-based composition

Parenteral formulations can be prepared as aqueous compositions using techniques known in the art. Typically, such compositions can be prepared as injectable preparations, for example, solutions or suspensions; solid forms suitable for preparation of solutions or suspensions upon addition of a reconstitution medium prior to injection; emulsions, such as water-in-oil ( w/o) emulsions, oil-in-water (o/w) emulsions and microemulsions thereof, liposomes or emulsomes.

The carrier can be a solvent or dispersion medium that contains or includes, for example, water, ethanol, one or more polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), oils, such as vegetable oils (such as peanut oil, corn oil, oil, sesame oil, etc.) and combinations thereof.

Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the desired particle size (for dispersions) and/or by the use of surfactants. In many cases, it will preferably include isotonic agents, for example, sugars or sodium chloride.

Solutions and dispersions of the active compounds as free acids or bases or pharmaceutically acceptable salts thereof may be prepared in water or other solvent or dispersion medium suitably mixed with one or more pharmaceutically acceptable Acceptable excipients include, but are not limited to, surfactants, dispersants, emulsifiers, pH adjusters, and combinations thereof.

Suitable surfactants may be anionic, cationic, amphoteric or nonionic. Suitable anionic surfactants include, but are not limited to, those containing or comprising carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long-chain alkyl sulfonic and alkylaryl sulfonic acids such as sodium dodecylbenzenesulfonate, sodium dialkyl succinates such as dodecylbenzenesulfonate, sodium phenyl sulfonate, sodium dialkyl sulfosuccinate, such as sodium bis-(2-ethylsulfoxy) sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, stearyldimethylbenzylammonium chloride, polyoxyethylene and coconut aminos. Examples of nonionic surfactants include: ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acrylate Alcohol Esters, Sucrose Acrylate, PEG-150 Laurate, PEG-400 Monolaurate, Polyoxyethylene Monolaurate, Polysorbate, Polyoxyethylene Octyl Phenyl Ether, PEG-1000 Cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, 401, stearyl monoisopropanolamide and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-lauryl-.β.-alanine, sodium N-lauryl-.β.-iminodipropionate, myristoamphoacetate, lauryl beet alkali and lauryl sultaine.

The formulations may contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid and thimerosal. The formulation may also contain antioxidants to prevent degradation of the active agent(s).

Formulations are typically buffered to a pH of 3-8 for parenteral administration upon reconstitution. Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers and citrate buffers.

Water soluble polymers are commonly used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose and polyethylene glycol.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent or dispersion medium with one or more of the above-listed excipients, if necessary, followed by filtration. Sterilize. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. For sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which yield the active ingredient plus any additional required ingredients in a previously sterile-filtered solution thereof. Ingredient powder. The powder can be prepared in such a way that the particles are made porous, which increases the dissolution of the particles. Methods of making porous particles are well known in the art.

a. Controlled release formulations

The parenteral formulations described herein can be formulated for controlled release, including immediate release, delayed release, extended release, pulsatile release, and combinations thereof.

Nano- and microparticles

For parenteral administration, the present compound, and optionally one or more additional active agents, may be incorporated into microparticles, nanoparticles or combinations thereof ensuring controlled release. In embodiments where the formulation contains two or more drugs, the drugs can be formulated for the same type of controlled release (e.g., delayed, extended, immediate or pulsatile) or the drugs can be formulated independently for different types of (e.g., immediate and delayed, immediate and extended, delayed and extended, delayed and pulsed, etc.).

For example, the compound and/or one or more additional active agents may be incorporated into polymer microparticles ensuring controlled release of the drug(s). Release of the drug(s) is controlled by diffusion of the drug(s) out of the microparticle and/or degradation of the polymer particles (by hydrolysis and/or enzymatic degradation). Suitable polymers include ethyl cellulose and other natural or synthetic cellulose derivatives.

Slowly dissolving and gel-forming polymers in aqueous environments such as hydroxypropylmethylcellulose or polyethylene oxide may also be suitable as materials for the microparticles containing or including the drug. Other polymers include, but are not limited to, polyanhydrides, poly(ester anhydrides), polyhydroxy acids such as polylactic acid (PLA), polyglycolic acid (PGA), poly(lactide-co-glycolide) (PLGA) , poly-3-hydroxybutyrate (PHB) and its copolymers, poly-4-hydroxybutyrate (P4HB) and its copolymers, polycaprolactone and its copolymers, and combinations thereof.

Alternatively, one or more drugs can be incorporated into microparticles prepared from materials that are insoluble or slowly soluble in aqueous solutions but are capable of utilizing surfaces in the gastrointestinal tract including enzymatic degradation, bile acid Active agent action and/or mechanical erosion to degrade. As used herein, the term "slowly soluble in water" refers to a substance that is insoluble in water within a period of 30 minutes. Preferred examples include fats, fatty substances, waxes, waxy substances and mixtures thereof. Suitable fats and fatty substances include fatty alcohols (such as lauryl, myristyl stearyl, cetyl or cetyl stearyl alcohol), fatty acids and derivatives including, but not limited to, fatty acid esters, fatty acid Glycerides (mono-, di- and tri-glycerides) and hydrogenated fats. Specific examples include, but are not limited to, hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenated castor oil, available under the trade name of hydrogenated oils, stearic acid, cocoa butter and stearyl alcohol. Suitable waxes and wax-like materials include natural or synthetic waxes, hydrocarbons and n-waxes. Specific examples of waxes include beeswax, glycowax, castor wax, carnauba wax, paraffin wax and candelilla wax. As used herein, a waxy material is defined as any material that is generally solid at room temperature and has a melting point of about 30 to 300°C.

In some cases, it may be desirable to vary the rate at which water penetrates the microparticles. For this purpose, rate controlling (wicking) agents may be formulated together with the fats or waxes listed above. Examples of rate-controlling materials include certain starch derivatives (such as waxy maltodextrin and drum-dried cornstarch), cellulose derivatives (such as hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose), alginic acid, lactose and talc. In addition, pharmaceutically acceptable surfactants (eg, lecithin) can be added to facilitate the degradation of such microparticles.

Water-insoluble proteins, such as zein, can also be used as materials for forming microparticles containing or including drugs. In addition, water-soluble proteins, polysaccharides, and their combinations can be formulated with drugs into microparticles and subsequently cross-linked to form insoluble networks. For example, cyclodextrins can be complexed with individual drug molecules and subsequently cross-linked.

Encapsulation or incorporation of the drug into a carrier material to produce microparticles containing or comprising the drug can be accomplished by known pharmaceutical formulation techniques. In the case of formulations in fats, waxes, or waxy materials, the carrier material is usually heated above its melting temperature and the drug is added to form a mixture comprising particles of the drug suspended in the carrier material, the drug included Dissolved in carrier material or mixed therewith. Subsequent formulation of the microparticles can be by several methods including, but not limited to, coagulation, extrusion, spray cooling, or water dispersion. In a preferred method, the wax is heated above its melting temperature, the drug is added, and the molten wax-drug mixture is allowed to coagulate with continued agitation as the wax-drug mixture cools. Alternatively, the molten wax-drug mixture can be extruded and pelletized to form pellets or beads. A detailed description of these methods can be found in "Remington - The science and practice of pharmacy", 20th ed., Jennaro et al., (Phila, Lippencott, Williams, and Wilkens, 2000).

For certain carrier materials, it may be desirable to use solvent evaporation techniques to produce microparticles containing or including the drug. In this case the drug is co-dissolved with the carrier material in a mutual solvent and the subsequent microparticle production can be by several techniques including, but not limited to, emulsion formation in water or other suitable medium, spray drying, or by The solvent was evaporated in , and the obtained material was milled.

In some embodiments, the drug is uniformly dispersed in a water-insoluble or slowly water-soluble material in particulate form. In order to minimize the size of the drug particles in the composition, the drug powder itself can be ground to produce fine particles prior to formulation. The method of jet milling, known in the pharmaceutical art, can be used for this purpose. In some embodiments, the drug in particulate form is uniformly dispersed in the wax or wax-like material by heating the wax or wax-like material above its melting point and adding the drug particles while stirring the mixture. In this case a pharmaceutically acceptable surfactant can be added to the mixture to facilitate dispersion of the drug particles.

The particles may also be coated with one or more modified release coats. Esters of solid fatty acids, which are hydrolyzed by lipase, can be sprayed onto microparticles or drug granules. Zein is an example of a naturally water-insoluble protein. It can be applied to microparticles or drug particles containing or comprising the drug by spraying or by wet granulation techniques. In addition to naturally water-insoluble materials, some substrates of digestive enzymes can be treated with a cross-linking process, resulting in the formation of an insoluble network. A number of methods have been reported for cross-linking proteins, which are initiated chemically and physically. One of the most common methods of obtaining crosslinks is the use of chemical crosslinkers. Examples of chemical crosslinking agents include aldehydes (glutaraldehyde and formaldehyde), epoxy compounds, carbodiimides, and genipin. In addition to these crosslinking agents, oxidized and natural sugars have been used to crosslink gelatin (Cortesi, R., et al., Biomaterials 19 (1998) 1641-1649). Crosslinking can also be accomplished using enzymatic means, for example transglutaminase has been approved as a GRAS substance for crosslinking seafood products. Finally, crosslinking can be initiated by physical means such as heat treatment, UV radiation and gamma radiation.

To produce a coating of cross-linked protein surrounding drug-containing microparticles or drug particles, a water-soluble protein can be sprayed onto the microparticles and subsequently cross-linked by one of the methods described above. Alternatively, microparticles containing or including the drug can be microencapsulated within the protein by coacervation-phase separation (eg, by addition of salt) and subsequently crosslinked. Some suitable proteins for this purpose include gelatin, albumin, casein and gluten.

Polysaccharides can also be cross-linked to form water-insoluble networks. For many polysaccharides, this can be accomplished by reacting with calcium salts or multivalent cations, which cross-link the polymer backbone. Pectin, alginate, dextran, amylose and guar gum are cross-linked in the presence of polyvalent cations. Complexes between oppositely charged polysaccharides can also be formed; pectin and chitosan, for example, can complex via electrostatic interactions.

3. Preparations for non-parenteral administration

Neuroactive steroids can be formulated for non-parenteral administration. Non-parenteral formulations may be for oral, subcutaneous, intraperitoneal, intramuscular, transdermal, nasal, pulmonary or mucosal delivery.

a. Long-acting preparations

Neuroactive steroids, including progesterone and progesterone analogs such as progesterone caprate, can be formulated as depot injections. In depot injections, the active agent is formulated with one or more pharmaceutically acceptable carriers that ensure gradual release of the active agent over hours or days after injection. Depot formulations may be administered by any suitable means, however, depot formulations are typically administered via subcutaneous or intramuscular injection.

Various carriers can be incorporated into depot formulations to ensure controlled release of the active agent. In certain instances, depot formulations contain one or more biodegradable polymeric or oligomeric carriers. Suitable polymeric carriers include, but are not limited to, poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid)-polyethylene glycol (PLA-PEG) block copolymers, poly(lactic acid) Anhydrides, poly(ester anhydrides), polyglycolic acid (PGA), poly-3-hydroxybutyrate (PHB) and its copolymers, poly-4-hydroxybutyrate (P4HB), polycaprolactone, cellulose , hydroxypropylmethylcellulose, ethylcellulose, and blends, derivatives, copolymers, and combinations thereof.

In depot formulations containing or comprising a polymeric or oligomeric carrier, the carrier and active agent may be formulated as a solution, emulsion or suspension. One or more neuroactive steroids, and optionally one or more additional active agents, may also be incorporated into polymeric or oligomeric microparticles, nanoparticles, or combinations thereof.

In certain instances, the formulation is fluid and designed to solidify or gel (ie, form a hydrogel or organogel) after injection. This may be the result of a change in the solubility of the composition after injection, or, for example, due to the injection of the prepolymer mixed with initiator and/or crosslinker. The polymer matrix, polymer solution or polymer particles entrap the active agent at the injection site. As the polymeric carrier gradually degrades, the active agent is released by diffusion of the agent out of the matrix and/or loss of the matrix as it is absorbed. The rate of release of the active agent from the injection site can be controlled, for example, by varying the chemical composition, molecular weight, cross-link density and concentration of the polymeric carrier. Examples of such systems include those described in US Patents 4,938,763, 5,480,656 and 6,113,943.

Depot preparations may also be prepared using other rate-controlling excipients, including hydrophobic materials, including acceptable oils (e.g., peanut oil, corn oil, sesame oil, cottonseed oil, etc.) and phospholipids, ion-exchange resins, and poorly soluble carriers .

The depot formulation may further contain a solvent or dispersion medium containing or including, for example, water, ethanol, one or more polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), oils, such as vegetable oils ( Such as peanut oil, corn oil, sesame oil, etc.) and combinations thereof. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the desired particle size (for dispersions) and/or by the use of surfactants. In many cases, it will preferably include isotonic agents, for example, sugars or sodium chloride.

Solutions and dispersions of the neuroactive compound as a free acid or base or a pharmacologically acceptable salt thereof may be prepared in water or other solvent or dispersion medium suitably mixed with one or more Pharmaceutically acceptable excipients, which include, but are not limited to, surfactants, dispersants, emulsifiers, pH regulators, and combinations thereof.

Suitable surfactants may be anionic, cationic, amphoteric or nonionic. Suitable anionic surfactants include, but are not limited to, those containing or comprising carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long-chain alkyl sulfonic and alkylaryl sulfonic acids such as sodium dodecylbenzenesulfonate, sodium dialkyl sulfosuccinates such as dodecylbenzenesulfonate sodium phenyl sulfonate, sodium dialkyl sulfosuccinate, such as sodium bis-(2-ethylsulfoxy) sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, stearyldimethylbenzylammonium chloride, polyoxyethylene and coconut aminos. Examples of nonionic surfactants include: ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acrylate Alcohol Esters, Sucrose Acrylate, PEG-150 Laurate, PEG-400 Monolaurate, Polyoxyethylene Monolaurate, Polysorbate, Polyoxyethylene Octyl Phenyl Ether, PEG-1000 Cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, 401, stearyl monoisopropanolamide and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-lauryl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl Sultaine.

The formulations may contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid and thimerosal. The formulation may also contain antioxidants to prevent degradation of the active agent(s).

Formulations are typically buffered to a pH of 3-8 for parenteral administration upon reconstitution. Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers and citrate buffers.

Water soluble polymers are commonly used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose and polyethylene glycol.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent or dispersion medium with one or more of the above-listed excipients, if necessary, followed by filtered sterilization . Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. For sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which yield the active ingredient plus any additional required ingredients in a previously sterile-filtered solution thereof. Ingredient powder. The powder can be prepared in such a way that the particles are made porous, which increases the dissolution of the particles. Methods of making porous particles are well known in the art.

b. gel

Formulations may be in the form of organogels (assuming the neuroactive steroid is relatively water insoluble) or hydrogels. Numerous gel formulations are known. See, eg, US Patent 5,411,737 to Hsu et al. Hydrogels may also be used, especially those that also include nanoparticle microparticles for sustained, immediate and/or delayed release. See, eg, US Patent 6,589,549 to Shih et al.

US Patent Application 20100295113 by Hoffman et al. describes a composite hydrogel comprising an aqueous solution of an anionic polysaccharide or its derivatives such as or its derivatives and an aqueous solution of methylcellulose or another water-soluble cellulose derivative thereof. Blends having dispersed polymer particles, such as polymer microparticles and nanoparticles, and wherein the stability of the hydrogel is enhanced relative to the stability of the hydrogel alone. The polymeric particles may contain at least one therapeutic agent, in which case the linear sustained release rate exhibited by each therapeutic agent may be adjusted or varied by selecting appropriate microparticle and/or nanoparticle polymer formulations. The composite can be injectable and can be used as a filler in the absence of a therapeutic agent for reconstructive and cosmetic procedures or can serve as a platform for subsequent delivery of a therapeutic agent.

See also, Salem, Int J Nanomedicine. 2010 Nov, 10;5:943-54, describing the administration of natural progesterone in sustained release form as intramuscular injection. A progesterone nanosuspension (PNS) was first developed and then dispersed in a thermosensitive gel matrix. The selected nanoparticles exhibited an average particle size of 267 nm and a zeta potential close to -41 mV. The in vitro release profile of PNS from PluronicF127 plus methylcellulose gel followed zero-order kinetics and was linearly related to the weight percent of gel dissolved, which confirmed that the overall rate of release of PNS was determined by pluronicF127/methylcellulose (MC) Gel dissolution controlled.

The gel can also be administered in combination with oral or subcutaneous application of the drug. See, eg, Tomic, et al., Gynecol Endocrinol. Apr. 19, 2011.

c. Oral preparations

Formulations are prepared using a pharmaceutically acceptable "carrier" whose constituent materials are believed to be safe and effective and which can be administered to an individual without causing unwanted biological side effects or unwanted interactions. A "carrier" is all ingredients present in a pharmaceutical formulation other than the active ingredient (at least one). The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, matrix-forming compositions and coating compositions.

"Carrier" also includes all components of the coating composition, which may include plasticizers, pigments, colorants, stabilizers and glidants. Preparation of delayed release dosage forms may be as described in, for example, "Pharmaceutical dosage form tablets", eds. Liberman et al. (New York, Marcel Dekker, Inc., 1989), "Remington - The science and practice of pharmacy" , 20th edition, Lippincott Williams & Wilkins, Baltimore, MD, 2000 and "Pharmaceutical dosage forms and drug delivery systems", 6th edition, Ansel et al. (Media, PA: Williams and Wilkins, 1995), which provides information on Information on carriers, materials, equipment and processes for the manufacture of tablets and capsules and delayed-release dosage forms of tablets, capsules and granules.

Examples of suitable coating materials include, but are not limited to, cellulosic polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate Acrylic acid esters and hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, acrylic polymers and copolymers, and can trade names (Roth Pharma, Westerstadt, Germany) Methacrylic resins, zein, shellac and polysaccharides.

In addition, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilizers, pore formers and surfactants.

Optional pharmaceutically acceptable excipients present in tablets, beads, granules or microgranules containing or including the drug include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants agents, stabilizers and surfactants. Diluents, also known as "fillers," are often necessary in order to increase the bulk of solid dosage forms to provide a practical size for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, Pre-gelatinized starch, silicon dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.

Binders are used to impart a cohesive quality to the solid dosage form, thus ensuring that the tablet or bead or granule remains intact after formation of the dosage form. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycols, waxes, natural and synthetic Gums such as acacia, tragacanth, sodium alginate, celluloses, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic and methacrylic acid copolymers, formazan Acrylic acid copolymer, methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone. Certain materials suitable as binders such as hydroxypropylmethylcellulose, ethylcellulose and microcrystalline cellulose may also be used as matrix-forming materials.

Lubricants are used to facilitate tablet manufacturing. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc and mineral oil.

Disintegrants are used to facilitate disintegration or "stopping" of the dosage form after administration and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose Vegetables, pregelatinized starch, clay, cellulose, arginine (alginine), gum (gum) or cross-linked polymers such as cross-linked PVP ( XL from GAF Chemical Corp).

Stabilizers are used to prevent or slow down drug decomposition reactions including, for example, oxidation reactions.

Surfactants may be anionic, cationic, amphoteric or nonionic. Suitable anionic surfactants include, but are not limited to, those containing or comprising carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium salts of long-chain alkyl sulfonic acids and alkylaryl sulfonic acids such as sodium dodecylbenzenesulfonate, sodium dialkyl succinates such as dodecylbenzenesulfonate, sodium alkylbenzene sulfonates, sodium dialkyl sulfosuccinates, such as sodium bis-(2-ethylsulfoxy) sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, stearyldimethylbenzylammonium chloride, polyoxyethylene and coconut aminos. Examples of nonionic surfactants include: ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acrylate Alcohol Esters, Sucrose Acrylate, PEG-150 Laurate, PEG-400 Monolaurate, Polyoxyethylene Monolaurate, Polysorbate, Polyoxyethylene Octyl Phenyl Ether, PEG-1000 Cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, 401, stearyl monoisopropanolamide and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-lauryl-.β.-alanine, sodium N-lauryl-.β.-iminodipropionate, myristoamphoacetate, lauryl beet alkali and lauryl sultaine.

Tablets, beads, granules or particles may, if desired, also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents and preservatives.

Delayed release moieties, designed to prevent drug release after a defined period of time. Although oral is not the preferred route of administration, in the case of oral release formulations the administration is in the upper gastrointestinal (GI) region. Delayed release in oral formulations can be achieved using enteric coatings. The enteric coated formulation remains intact or substantially intact in the stomach once it reaches the small intestine to dissolve and release the contents of the dosage form. Other types of coatings may be used to ensure delayed release following subcutaneous, intratissue or intramuscular injection at or near the site in need of treatment.

extended release dosage form

Extended release formulations are usually prepared as diffusive or osmotic systems, eg, as described in "Remington—The science and practice of pharmacy" (20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000). Diffusion systems typically consist of two types of devices, reservoirs and substrates, which are well known and described in the art. Matrix devices are typically prepared by compressing the drug and a slowly dissolving polymeric carrier into a tablet. The main three types of substances used in making matrix devices are insoluble plastics, hydrophilic polymers, and aliphatic compounds. Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkyl celluloses such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and 934, polyethylene oxide and their mixtures. Fatty compounds include, but are not limited to, various waxes such as carnauba wax and tristearin, and waxy materials including hydrogenated castor oil or hydrogenated vegetable oils or mixtures thereof.

In some preferred embodiments, the plastic substance is a pharmaceutically acceptable acrylic polymer including, but not limited to, acrylic and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymer, methacrylic acid Ethoxyethyl ester, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), alkylamine methacrylate copolymer poly(methyl methacrylate esters), poly(methacrylic acid)(anhydride), polymethacrylates, polyacrylamides, poly(methacrylic anhydride), and glycidyl methacrylate copolymers.

In some preferred embodiments, the acrylate polymer comprises one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylate esters with low levels of quaternary ammonium groups.

In a preferred embodiment, the acrylic polymer is an acrylic lacquer such as that sold commercially by RohmPharma under the tradename acquired ones. In a further preferred embodiment, the acrylic polymer comprises commercially available from Rohm Pharma under the trade name RL30D and A mixture of two acrylic paints sold by RS30D. RL30D and .RS30D is a copolymer of acrylic acid and methacrylate with low content of quaternary ammonium group, in which The molar ratio of the ammonium group to the remaining neutral (meth)acrylate in RL30D is 1:20, while in In RS30D, it is 1:40. The average molecular weight is about 150,000. also preferred S-100 and L-100. The designations RL (high permeability) and RS (low permeability) refer to the osmotic properties of these agents. The RL/RS mixture is insoluble in water and digestive fluids. However, the resulting multiparticulate systems containing it are swellable and permeable in aqueous and digestive fluids.

The aforementioned polymers such as RL/RS can be mixed together in any desired ratio to finally obtain a sustained release formulation with the desired dissolution profile. can be made by e.g. 100% RL, 50% RL and 50% RS, and 10% RL and 90% RS obtains the desired sustained release multiparticulate system. Those skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, L.

Alternatively, extended-release formulations can be prepared using osmotic systems or by applying semi-permeable coatings to the dosage form. In the latter case. The desired drug release profile can be achieved by combining low osmotic and high osmotic coating materials in appropriate ratios.

Devices having the different drug release mechanisms described above may be combined into a final dosage form comprising single or multiple units. Examples of multiple units include, but are not limited to, multilayer tablets and capsules that contain or include tablets, beads, or granules.

The immediate release layer may be applied by coating or tableting methods either on top of an extended release core or in a multi-unit system such as a capsule containing or including extended and immediate release beads, whereby The immediate release portion is added to the extended release system.

Extended release tablets containing or comprising a hydrophilic polymer are prepared according to techniques well known in the art, such as direct compression, wet granulation or dry granulation. Their formulations typically incorporate polymers, diluents, binders and lubricants, and active pharmaceutical ingredients. Common diluents include inert powdered substances such as starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, fine flour, and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives can also be used. Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, glucose. Natural and synthetic gums can also be used, including acacia, alginate, methylcellulose, and polyvinylpyrrolidone. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also be used as binders. Lubricants are necessary in tablet formulations to prevent the tablet and punch from sticking to the die. Lubricants are selected from lubricating solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

Extended release tablets containing or including waxy substances are generally prepared using methods known in the art, such as direct mixing, congealing and aqueous dispersion. In coagulation, the drug is mixed with a waxy substance and either spray coagulated or coagulated and screened and processed.

delayed release dosage form

Delayed release formulations are produced by coating a solid dosage form with a polymer film that is insoluble in the acidic environment of the stomach but soluble in the neutral environment of the small intestine.

For example, delayed release dosage units can be prepared by coating the drug, or compositions containing or comprising the drug, with a coating of choice. The composition containing or comprising the drug may be, for example, a tablet for incorporation into a capsule, a tablet used as the inner core of a "coated core" dosage form, or a plurality of tablets for incorporation into a tablet or capsule Beads, microparticles or granules containing or comprising a drug. Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble and/or enzymatically degradable polymers, and may be conventional "enteric" polymers. Those skilled in the art will recognize that enteric polymers become soluble in the higher pH environment of the lower GI tract, or slowly erode as the dosage form passes through the GI tract, while enzymatically degradable polymers pass through the lower GI tract. degraded by bacterial enzymes present in the tract, especially the colon. Suitable coating materials to produce delayed release include, but are not limited to, cellulosic polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethyl acetate Cellulose Succinate, Hydroxypropyl Methyl Cellulose Phthalate, Methyl Cellulose, Ethyl Cellulose, Cellulose Acetate, Cellulose Acetate Phthalate, Cellulose Acetate Trimellitate esters and sodium carboxymethylcellulose; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and/or ethyl methacrylate, and trade name Other commercially available methacrylic resins from (Rohm Pharma; Westerstadt, Germany) include L30D-55 and L100-55 (soluble at pH 5.5 and above), L-100 (soluble at pH 6.0 and above), S (soluble at pH 7.0 and above, which is a result of a higher degree of esterification), and NE, RL and RS (water-insoluble polymers with varying degrees of permeability and swelling); vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymer and ethylene-vinyl acetate copolymers; enzymatically degradable polymers such as azopolymers, pectin, chitosan, amylose, and guar gum; zein and shellac. Combinations of different coating substances may also be used. Multiple coatings using different polymers are also suitable.

A person skilled in the art can readily determine the preferred coating weight for a particular coating material by evaluating the respective release profiles of tablets, beads and granules prepared with different amounts of each coating material. The combination of substances, methods and forms employed to produce the desired release profile can be determined solely on the basis of clinical studies.

The coating composition may include conventional additives such as plasticizers, pigments, colorants, stabilizers, glidants and the like. Plasticizers are generally present to reduce the brittleness of the coating and will typically be present in an amount of about 10% to 50% by weight relative to the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate , triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil and acetylated monoglycerides. Stabilizers are preferably used to stabilize the microparticles in the dispersion. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended for reducing sticking effects during film formation and drying, and typically comprise from about 25% to 100% by weight of the polymer in the coating solution. An effective glidant is talc. Other glidants such as magnesium stearate and glyceryl monostearate may also be used. Pigments such as titanium dioxide may also be used. Small amounts of anti-foaming agents such as silicones (eg polydimethylsiloxane) may also be added to the coating composition.

Manufacturing method

As understood by those skilled in the art and as described in the relevant text and literature, a number of methods can be used to prepare tablets, beads, granules or microgranules containing or comprising a drug that provide various drug release profiles. Such methods include, but are not limited to, the following: coating the drug or a composition containing or comprising the drug with a suitable coating material, typically but not necessarily incorporating a polymeric material to increase the particle size of the drug, placing the drug in a matrix, And form drug complexes with appropriate complexing agents.

The delayed-release polymer can be coated with a delayed-release polymer using conventional techniques, such as using conventional coating pans, airless spray techniques, fluidized bed coating equipment (with or without Wurster inserts), and the like. dosage unit. For details on materials, equipment, and methods for preparing tablets and delayed-release dosage forms, see Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and Ansel et al., Pharmaceutical Dosage Forms Forms and Drug Delivery Systems, 6.sup.thEd. (Media, PA: Williams & Wilkins, 1995).

Alternatively, delayed-release tablets can be formulated by dispersing the drug within a matrix of suitable materials, such as hydrophilic polymers or fatty compounds. Hydrophilic polymers may include polymers or copolymers of cellulose, cellulose esters, acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, and vinyl, or enzymatically degradable polymers or copolymers, as described above . These hydrophilic polymers are particularly useful for providing delayed release matrices. Fatty compounds useful as matrix materials include, but are not limited to, waxes such as carnauba wax and glycerol tristearate. Once the active ingredient is mixed with the base material, the mixture can be compressed into tablets.

A preferred method of preparing extended release tablets is to compress a mixture containing or comprising the drug, eg a mixture of granules, which is prepared by direct mixing, wet granulation, or dry granulation techniques. Extended release tablets may also be molded from a moist mass with or including a suitable water-soluble lubricant rather than compressed. However, it is preferred to make tablets by compression rather than molding. A preferred method of forming an extended release mixture containing or comprising a drug is by directly mixing the drug microparticles with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, excipients, etc. Fluids and colorants. As an alternative to direct blending, admixtures containing or including the drug can be prepared by using wet granulation, or dry granulation processes. Beads containing or including the active agent can also be prepared by any of a number of conventional techniques, typically starting from a fluid dispersion. For example, a typical method of preparing beads containing or including a drug involves dispersing or dissolving the active agent in a coating suspension or solution containing or including a drug excipient such as polyvinylpyrrolidone, methylcellulose, talc, Metal stearate, silicon dioxide, plasticizers, and the like. This mixture is used to coat the cores of beads, such as sugar spheres (or so-called "non-pareil") of about 60 to 20 mesh size.

An alternative method of preparing drug beads is to mix the drug with one or more pharmaceutically acceptable excipients such as microcrystalline cellulose, lactose, cellulose, polyvinylpyrrolidone, talc, magnesium stearate, disintegrant, solution, etc., the mixture is extruded, the extrudate is pelletized, dried and optionally coated to form immediate release beads.

d. Implants

Neuroactive steroids can also be administered by inserting implants such as silicone rubber tubes used to deliver contraceptive hormones. See, eg, Levonorgestrel and Norplant, both of which deliver long-term release contraceptive hormones after subcutaneous implantation. The effective dose is increased by increasing the size of the pore through which the drug exits the reservoir to the individual to be treated.

e. Transdermal patches

Neuroactive steroids can also be administered via transdermal patches, similar to those used for contraception, but at significantly higher doses. See eg, Transdermal CombiPatch (Estradiol/Norethindrone) and Testogen ^™ - Enhanced testosterone. The dose can be increased by increasing the release mechanism and/or increasing the concentration in the patch.

D. Combinations with other active compounds

Neuroactive steroids may be administered additionally with other active compounds such as analgesics, anti-inflammatories, antipyretics, antiepileptics, antihistamines, antimigraines, antimuscarinics, anxiolytics, sedatives , hypnotics, antipsychotics, bronchodilators, anti-asthmatics, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, parasympathomimetics, stimulants, anorectics, and antinarcolepsy drugs.

All cited publications are incorporated by introduction.

III. Administration of Neuroactive Steroid Preparations

The compositions described herein can be administered to a subject in need thereof to treat a disorder, e.g., a CNS-related disorder, e.g., traumatic brain injury; e.g., convulsive status epilepticus, e.g., early epilepsy Status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; nonconvulsive status epilepticus, eg, generalized status epilepticus, complex partial status epilepticus; seizures, eg, Acute recurrent seizures, intensive seizures. Although the preferred patient is a human, generally any mammal, including domestic animals such as dogs, cats and horses, can also be treated.

traumatic brain injury

The amount of active ingredient to be administered is selected on the basis of that amount to provide the desired dose to a patient in need of such treatment to alleviate symptoms or treat a condition. Behavioral analysis can be used to determine the rate and extent of behavioral recovery in response to treatment. Improved patient motor capacity, spatial learning performance, cognitive function, sensory perception, language and/or reduction in seizure propensity can also be used to measure neuroprotection. Such functional/behavioral tests for evaluating sensorimotor and reflex function are described, for example, in Bederson et al. (1986) Stroke 17:472-476, DeRyck et al. (1992) Brain Res. 573:44-60, Markgraf et al. ) Brain Res. 575:238-246, in Alexis et al. (1995) Stroke 26:2336-2346. Enhancement of neuronal survival can also be measured using the Scandinavian Stroke Scale (SSS) or the Barthl index. Treatment of traumatic brain injury can be monitored using various neurological measures. For example, local treatment response can be monitored, for example, by determining whether there is an improvement in the subject: a) daily Glasgow Coma Scale maximum; b) duration of coma; 3) daily intracranial pressure-treatment intensity rating ; 4) the extent of cerebral edema/mass impact as measured on serial CT scans; and 5) the duration of ventilator support. A brief description of each of these assays is provided below.

The Glasgow Coma Scale (Index GCS) reflects the depth of disturbance of consciousness and is best obtained after initial resuscitation (oxygenation, fluids, and blood pressure support) but before the use of sedatives, neuromuscular blocking agents, or endotracheal intubation.

Coma duration was defined as the number of hours during which the subject was unable to respond purposefully to commands or impairments of mechanical stimuli. For non-intubated subjects, this equates to a GCS score of >8. For intubated patients, this correlates with the GCS motor score from .gtoreq.5. Coma duration was found to be predictive of functional pathological outcomes (Uhler et al. (1994) Neurosurgery 34(1):122-8; Jiang et al. (1996) Brain Res 735(1):101-7; and Gonzalez-Vidal et al. (1998) Arch Med Res 29(2):117-24). Time spent in a pharmacologically induced coma for reasons other than brain injury should be subtracted in the final analysis. Intracranial pressure (ICP) in patients with severe TBI is usually monitored with ICP equipment. Monitoring ICP can provide a measure of cerebral edema. However, inherent variability and analytical complexity arise from therapeutic interventions aimed at reducing ICP risk (measured using ICP). To regulate these interventions, a treatment intensity scale was developed. This scale, called Treatment Intensity Level (TIL), measures aggressive treatment of elevated ICP (Allolio et al (1995) European Journal of Endocrinology 133(6):696-700; Adashi et al (1996) Reproductive endocrinology , surgery, and technology Philadelphia: Lippincott-Raven; and Beers et al. (1999) The Merck manual of diagnosis and therapy. 17th ed., edited by Beers et al., Merck Sharp & Dohme Research Laboratories, Rahway, N.J.). The degree of brain edema and mass influence can be determined by CT scan. For example, the volume of a lesion can be measured. Massive lesions, whether hyperdense or mixed attenuated abnormalities, can be evaluated by measuring the area of abnormality as the area of interest, multiplying this area by the slice thickness and summing their values for adjacent slices showing the same lesion. volume. Three measurements will be taken for each lesion and the average volume will be entered. This technique proved to be reliable (Garcia-Estrada et al. (1993) Brain Res 628(1-2):271-8).

Intracerebral lesions can be further characterized by location (frontal, temporal, parietal, occipital, basal ganglia, or any combination). When an edematous area is present, its volume (hypodense periphery) can be measured and analyzed separately. Midline shift can be measured by using the septum pellucida as a midline construct. Ventricular-to-brain ratio (VBR) was calculated to quantify the degree of brain atrophy. Levin et al. ((1981) Archives of Neurology 38(10):623-9) found that VBR also had satisfactory reliability across different examiners and correlated with both acute injury severity and neurobehavioral sequelae (Hoffman et al. (1994) J Neurotrauma 11(4):417-31). The duration of ventilator support can be defined as the number of hours a patient receives positive pressure mechanical ventilation (Uhler et al (1994) Veurosurgery 34(1):122-8; Jiang et al (1996) Brain Res 735(1):101-7; and Gonzalez-Vidal et al. (1998) ArchMed Res 29(2):117-24). Time spent on ventilator support for reasons other than brain injury will be subtracted from the final analysis. In addition to the neurological measures discussed above, local treatment response can also be examined by various functional and neuropsychological outcomes. Several standardized measures of neuropsychological and functional performance are known. For example, a subject may show improvement in Glasgow Outcome Scale (GOS)/Glasgow Outcome Scale Extended (GOSE) and/or Disability Rating Scale (DRS). The Glasgow Outcome Scale is one of the most widely used measures of brain injury recovery in the world (Garcia-Estrada et al (1999) Int J Dev Neurosci 17(2):p. 145-51).

Patients were classified into one of five categories: dead, vegetative state, severely disabled, moderately disabled, and well recovered. It is easy to implement and score, and has a high degree of reliability and validity. The Disability Rating Scale (DRS) provides greater precision than the GOS for measuring prognosis in moderate brain injury (Goodman et al. (1996) J Neurochem 66(5):1836-44). The DRS consists of an eight-item score of arousal and cognition, activities of daily living, physical dependence, and employability (Vedder et al. (1999) JNeurochem 72(6):2531-8). Inter-rater reliability across the DRS was high (0.97 to 0.98). The Functional Independence Measure (FIM) can be used to assess physical and cognitive disabilities. It contains 18 items in the following areas: self-care, sphincter control, mobility, movement, communication, and social cognition (Baulieu (1997) MultScler 3(2):105-12). FIM has shown reliability and validity as a prognostic measure following moderate and severe TBI (Jung-Testas et al. (1994) J Steroid Biochem Mol Biol 48(1):145-54).

The Disease Impact Scale is a method of measuring self-perceived health status (Schumacher et al. (1995) Ciba Found Symp 191: p.90-112 and Koenig et al. (1995) Science 268(5216): 1500-3). It includes 136 questions divided into 12 categories: sleep and rest, diet, work, home management, leisure and recreation, walking, mobility, body care and exercise, social interaction, alertness, behaviour, emotional behavior and communication. It is used in a wide variety of diseases and injuries, including head injuries (Thomas et al. (1999) Spine 24:2134-8). Baseline SIP scores reflect pre-injury health status, while follow-up scores examine post-injury function. ischemia

Global cerebral ischemia involving the CNS, as used herein, refers to a disorder resulting from a general decrease in blood flow throughout the brain, forebrain or spinal cord, which results in neurons (especially those metabolically active sites) in these tissues delayed death. Focal cerebral ischemia involving the CNS, as used herein, refers to a disorder resulting from the blockage of a single artery supplying blood to the brain or spinal cord, which results in the loss of all cellular components (pancreas) in the area supplied by that artery. necrosis) death.

epilepsy

Epilepsy is a brain disorder characterized by repeated seizures over a defined period of time. Types of epilepsy may include, but are not limited to, generalized epilepsy, e.g., childhood absence epilepsy, juvenile myoclonic epilepsy, arousal grand mal epilepsy, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g. , Temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy in children. Status epilepticus (SE)

Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, treatment-refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as Generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus seizures and can include early status epilepticus, established status epilepticus, treatment-refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. The establishment of status epilepticus is characterized by persistent status epilepticus seizures despite implementation of treatment with first-line and second-line therapy. Refractory status epilepticus is characterized by persistent status epilepticus seizures despite generally performed treatment with first-line and second-line therapy and conventional anesthetics. Ultra-refractory status epilepticus is characterized by persistent status epilepticus seizures despite treatment with first-line and second-line therapy and conventional anesthetics for 24 hours or more. Nonconvulsive status epilepticus can include, e.g., focal nonconvulsive status epilepticus, eg, complex partial nonconvulsive status epilepticus, simple partial nonconvulsive status epilepticus, minimal nonconvulsive status epilepticus Generalized nonconvulsive status epilepticus, such as delayed absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus.

Compositions described herein may also be administered as prophylaxis to subjects with central nervous system disorders, e.g., traumatic brain injury, status epilepticus, e.g., convulsive epilepsy, prior to the onset of seizures Status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; nonconvulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus state; systemic periodic epileptiform discharges; and periodic unilateral epileptiform discharges.

epileptic seizure

Seizures as described herein may include seizures; acute recurrent seizures; clustered seizures; continuous seizures; uninterrupted seizures; prolonged seizures; periodic seizures; status epilepticus, e.g., refractory Convulsive status epilepticus, non-convulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; Secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; jerking seizures; generalized primary seizures; Infantile spasms; Jacksonian seizures; bilateral giant myoclonic seizures; multifocal seizures; neonatal seizures; nocturnal seizures; occipital lobe seizures; posttraumatic seizures; microscopic seizures; Sylvan seizures; Visual reflex seizures; or withdrawal seizures. The invention is further described with reference to the following non-limiting examples.

Example 1. Including Isopregnanolone and Stability studies of formulations

Raw Materials and Methods

Isopregnanolone (1.5mg/ml) and (6%) formulations were evaluated for stability after storage for 12 weeks at different temperatures and relative humidity. The formulation is stored in Intra Via flexible bags [multilayer polyolefin plastic, (PL2408), non-latex, non-PVC, non-DEHP] or vials (glass vials of size 1 with 20 mm stoppers, FluroTec, 4432/50Westar). The sample consists of 250ml stock solution (6mg/ml isopregnalone/ )preparation. Formulations were evaluated based on clarity/color, analysis (potency), impurities (known, unknown and total), osmolality, pH, bacterial endotoxin and particulate matter.

result

The study showed that the formulation was stable under all conditions tested for twelve weeks: refrigerated 2-5°C; refrigerated 25°C/50%RH; refrigerated 40°C/75%RH; refrigerated 60°C; refrigerated 2-5°C ; Refrigerated 25°C/60%RH; Refrigerated 40°C/75%RH; and Refrigerated 60°C.

Example 2. Isopregnanolone rescue by AGSSE in Fmr1 knockout mice.

Isopregnanolone in 30% β-cyclodextrin reversed audiogenic seizures (AGS) in Fmr1 knockout mice at 3, 10, 30 mg/kg intraperitoneal (IP) doses (a Sensitization of the status epilepticus (SE) form), as indicated by a significant decrease in the percentage of seizures (Fig. 1A) and an increase in the percentage of survival relative to vehicle-treated controls (Fig. 1B). Plasma levels were randomly collected from six animals in the respective isopregnolone treatment groups at study completion and analyzed by LC-MS/MS. Bioanalytical measurements are shown in ng/mL (Figure 1A). Data are expressed as mean +/- SEM. *P<0.05 indicates statistically significant difference by Fisher's PLSD relative to vehicle control. MPEP 30 mg/kg was used as a positive control in the study.

Example 3. Isopregnanolone prevents status epilepticus in the PZT-seizure model.

Isopregnolone in 15% β-cyclodextrin at 3, 10, 30 mg/kg intraperitoneal (IP) doses to prevent PTZ (pentetrazol) (85 mg/kg IP)-treated C57BL6/ Status epilepticus in J mice, as represented by a significant reduction in seizure grade (Figure 2A), and an increase in latency to death (Latency to Death) relative to vehicle-treated controls (Fig. 2B). Plasma levels were randomly collected and analyzed by LC-MS/MS from three animals in the respective isopregnalone treatment groups at study completion. Bioanalytical measurements are shown in ng/mL (Figure 2A). Data are expressed as mean +/- SEM. *P<0.05 indicates statistically significant difference by Fisher's PLSD relative to vehicle control. Valproate (Valproate) 400 mg/kg was used as a positive control in the study.

Example 4. Plasma concentrations of isopregnalone in treatment-refractory status epilepticus.

Evaluation of the plasma concentration profile of isopregnolone over time in male patients diagnosed with refractory status epilepticus is shown in FIG. 3 . The patient was administered isopregnalone (1.5 mg/ml in 6% hydroxypropyl-beta-cyclodextrin/0.9% sodium chloride) intravenously for 5 days. The infusion rate was 86 μg/kg/h. The dosing regimen consisted of 5.6 mg/h isopregnanolone administered at 3.8 mL/h. Plasma concentrations were analyzed 2 hours before the start of the infusion and then at 52, 76, 100, 124 and 148 hours.

Example 5. In vivo plasma concentrations of isopregnalone after intramuscular and intravenous administration.

In SD rats in a single intramuscular (IM) (10mg/kg) or intravenous (IV) (5mg/kg) at 30% Plasma and brain exposure profiles of isopregnalone measured by LC/MS-MS following drug administration. Analysis showed: relative to the IV (5 mg/kg) dose, IM administered isopregnanolone (10 mg/kg) had an unexpected substantially greater plasma exposure (671-916%, 0.5-2 hours) and brain exposure (506%, 1 hour), as indicated in Tables 1 and 2. N=2/time point. Error bars, SEM (Figures 4A and 4B).

Example 6. At 6% Progesterone rescues injury in a rodent model of TBI .

In the penetrating ballistic brain injury rodent model of traumatic brain injury (penetrating ballisticbrain injury rodent model), in the low and high dose groups (Figure 5A and Figure 5B), 6% Progesterone rescue exercise damage in progesterone. Progesterone was administered via a bolus injection loading dose followed by 5 days of continuous infusion with a 25% taper of progesterone every 8 hours over the final 24 hour period. The low-dose group received a 2.5 mg/kg/hr bolus infusion over 1 hour, followed by a maintenance dose of 1.25 mg/kg/hr over 5 days, with a taper over the last 24 hours. The high-dose group received a 5.0 mg/kg/hr bolus infusion for 1 hour, followed by a maintenance dose of 2.50 mg/kg/hr over 5 days, with a final 24-hour taper.

It is to be understood that the disclosed invention is not limited to the particular methodology, protocols and reagents described, which may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope, which will be limited only by the appended claims. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing, the preferred methods, devices and materials are as described. Publications cited herein and the materials for which they are cited are expressly incorporated by reference.

Claims (42)

1. A method of treating traumatic brain injury, comprising: administering to a subject in need thereof a dosage form of an effective amount of an isopregnanolone in a cyclodextrin carrier for the treatment of central nervous system injury.

2. The method of claim 1, wherein said allopregnanolone is administered according to a therapeutically effective two-stage dosing regimen of allopregnanolone comprising: a first time period wherein a first hourly dose of the allopregnanolone is administered to the subject, followed by a second time period wherein a lower hourly infusion dose of the allopregnanolone is administered.

3. The method of claim 2, wherein the allopregnanolone is administered a loading dose over 1 hour, followed by a maintenance infusion over the next 95 hours, and then gradually reduced by decreasing the dose.

4. The method of claim 1, wherein the allopregnanolone is administered over five days.

5. The method of claim 1, wherein the concentration of the allopregnanolone is from about 0.25mg/mL to about 15 mg/mL.

6. The method of claim 1, wherein the concentration of said allopregnanolone is about 1.5 mg/ml.

7. The method of claim 1, wherein said dose of isopregnanolone administered by infusion results in a steady state serum isopregnanolone concentration of about 150nM to 2500 nM.

8. The method of claim 1, wherein the allopregnanolone (3 α,5 α -tetrahydroprogesterone) is formulated with 6% pharmaceutical grade sulfobutylether- β -cyclodextrin (SBE β CD).

9. The method of claim 1, wherein the allopregnanolone (3 α,5 α -tetrahydroprogesterone) is formulated with 15% pharmaceutical grade sulfobutylether- β -cyclodextrin (SBE β CD).

10. The method of claim 1, wherein the allopregnanolone (3 α,5 α -tetrahydroprogesterone) is formulated with 30% pharmaceutical grade sulfobutyl ether- β -cyclodextrin (SBE β CD).

11. A pharmaceutical dosage unit comprising a complex of an isopregnanolone and a cyclodextrin.

12. The dosage unit of claim 11, wherein the allopregnanolone is selected from the group consisting of allopregnanolone and its salts and enantiomeric forms.

13. The dosage unit of claim 11, wherein the cyclodextrin is selected from the group consisting of cyclic oligosaccharides containing or comprising six (α -cyclodextrin), seven (β -cyclodextrin), eight (γ -cyclodextrin) or more α - (1,4) -bonded glucose residues and chemically modified cyclodextrins.

14. The dosage unit of claim 11, wherein the cyclodextrin is selected from the group consisting of alpha-cyclodextrin; beta-cyclodextrin; gamma-cyclodextrin; methyl alpha-cyclodextrin; methyl beta-cyclodextrin; methyl gamma-cyclodextrin; ethyl beta-cyclodextrin; butyl α -cyclodextrin; butyl beta-cyclodextrin; butyl gamma-cyclodextrin; amyl gamma-cyclodextrin; hydroxyethyl beta-cyclodextrin; hydroxyethyl gamma-cyclodextrin; 2-hydroxypropyl α -cyclodextrin; 2-hydroxypropyl β -cyclodextrin; 2-hydroxypropyl gamma-cyclodextrin; 2-hydroxybutyl β -cyclodextrin; acetyl alpha-cyclodextrin; acetyl beta-cyclodextrin; acetyl gamma-cyclodextrin; propionyl beta-cyclodextrin; butyryl β -cyclodextrin; succinyl α -cyclodextrin; succinyl beta-cyclodextrin; succinyl gamma-cyclodextrin; benzoyl beta-cyclodextrin; palmityl beta-cyclodextrin; tosyl β -cyclodextrin; acetyl methyl beta-cyclodextrin; acetyl butyl beta-cyclodextrin; glucosyl alpha-cyclodextrin; glucosyl beta-cyclodextrin; glucosyl gamma-cyclodextrin; maltosyl alpha-cyclodextrin; maltosyl beta-cyclodextrin; maltosyl gamma-cyclodextrin; α -cyclodextrin carboxymethyl ether; beta-cyclodextrin carboxymethyl ether; gamma-cyclodextrin carboxymethyl ether; carboxymethylethyl beta-cyclodextrin; phosphate ester alpha-cyclodextrin; phosphate beta-cyclodextrin; phosphate ester gamma-cyclodextrin; 3-trimethylammonium-2-hydroxypropyl β -cyclodextrin; sulfobutyl ether beta-cyclodextrin; carboxymethyl alpha-cyclodextrin; carboxymethyl β -cyclodextrin; carboxymethyl gamma-cyclodextrin, alkyl cyclodextrins, hydroxyalkyl cyclodextrins, carboxyalkyl cyclodextrins, and sulfoalkyl ether cyclodextrins, and combinations thereof.

15. The pharmaceutical dosage unit of claim 11, comprising a complex of 3 α,5 α -tetrahydroprogesterone and sulfobutyl ether- β -cyclodextrin (SBE β CD).

16. The pharmaceutical dosage unit of claim 15, comprising 3 α,5 α -tetrahydroprogesterone formulated in 0.9% sterile sodium chloride with or including 6% pharmaceutical grade sulfobutyl ether- β -cyclodextrin (SBE β CD).

17. The pharmaceutical dosage unit of claim 15, comprising 3 α,5 α -tetrahydroprogesterone formulated in 0.9% sterile sodium chloride including 15% pharmaceutical grade sulfobutylether- β -cyclodextrin (SBE β CD).

18. The pharmaceutical dosage unit of claim 15, comprising 3 α,5 α -tetrahydroprogesterone formulated in 0.9% sterile sodium chloride including 30% pharmaceutical grade sulfobutylether- β -cyclodextrin (SBE β CD).

19. A method of treating a central nervous system disorder, comprising: a dosage form of an effective amount of an isopregnanolone in a cyclodextrin carrier is administered to a subject.

20. The method of claim 19, wherein said allopregnanolone is administered according to a therapeutically effective two-stage dosing regimen of allopregnanolone comprising: a first time period wherein a first hourly dose of the allopregnanolone is administered to the subject, followed by a second time period wherein a lower hourly infusion dose of the allopregnanolone is administered.

21. The method of claim 20, wherein the allopregnanolone is administered a loading dose over 1 hour, followed by a maintenance infusion over the next 95 hours, and then gradually reduced by decreasing the dose.

22. The method of claim 19, wherein the allopregnanolone is administered over five days.

23. The method of claim 19, wherein the concentration of the allopregnanolone is from about 0.25mg/mL to about 15 mg/mL.

24. The method of claim 19, wherein the concentration of the isopregnanolone is about 1.5 mg/mL.

25. The method of claim 19, wherein said dose of isopregnanolone administered by infusion results in a steady state serum isopregnanolone concentration of about 150nM to 2500 nM.

26. The method of claim 19, wherein the allopregnanolone (3 α,5 α -tetrahydroprogesterone) is formulated with 6% pharmaceutical grade sulfobutylether- β -cyclodextrin (SBE β CD).

27. The method of claim 19, wherein the allopregnanolone (3 α,5 α -tetrahydroprogesterone) is formulated with 15% pharmaceutical grade sulfobutylether- β -cyclodextrin (SBE β CD).

28. The method of claim 19, wherein the allopregnanolone (3 α,5 α -tetrahydroprogesterone) is formulated with 30% pharmaceutical grade sulfobutylether- β -cyclodextrin (SBE β CD).

29. The method of claim 19, wherein the central nervous system disorder is status epilepticus.

30. The method of claim 29, wherein the status epilepticus disorder is refractory status epilepticus.

26. The method of claim 19, wherein the status epilepticus disorder is a non-convulsive status epilepticus.

27. The method of claim 19, wherein the central nervous system disorder is traumatic brain injury.

28. The method of claim 19, wherein the central nervous system disorder is a seizure.

29. The method of claim 19, wherein the seizure is acute recurrent seizures or intensive seizures.

30. A method of treating a central nervous system disorder, comprising: administering to the subject an effective amount of the allopregnanolone dosage formulation, wherein the central nervous system disorder is a seizure or status epilepticus.

31. The method of claim 30, wherein the disorder is status epilepticus.

32. The method of claim 30, wherein the status epilepticus disorder is refractory status epilepticus.

33. The method of claim 30, wherein the status epilepticus disorder is a non-convulsive status epilepticus.

34. The method of claim 30, wherein said allopregnanolone is administered according to a therapeutically effective two-stage dosing regimen of allopregnanolone comprising: a first time period wherein a first hourly dose of the allopregnanolone is administered to the subject, followed by a second time period wherein a lower hourly infusion dose of the allopregnanolone is administered.

35. The method of claim 34, wherein the allopregnanolone is administered a loading dose over 1 hour, followed by a maintenance infusion over the next 95 hours, and then gradually reduced by decreasing the dose.

36. The method of claim 30, wherein the allopregnanolone is administered over five days.

37. The method of claim 30, wherein the concentration of the allopregnanolone is from about 0.25mg/mL to about 15 mg/mL.

38. The method of claim 30, wherein the concentration of the isopregnanolone is about 1.5 mg/mL.

39. The method of claim 30, wherein said dose of isopregnanolone administered by infusion produces a steady state serum isopregnanolone concentration of about 150nM to 2500 nM.

40. The method of claim 30, wherein the allopregnanolone (3 α,5 α -tetrahydroprogesterone) is formulated with 6% pharmaceutical grade sulfobutylether- β -cyclodextrin (SBE β CD).

41. The method of claim 30, wherein the allopregnanolone (3 α,5 α -tetrahydroprogesterone) is formulated with 15% pharmaceutical grade sulfobutylether- β -cyclodextrin (SBE β CD).

42. The method of claim 30, wherein the allopregnanolone (3 α,5 α -tetrahydroprogesterone) is formulated with 30% pharmaceutical grade sulfobutylether- β -cyclodextrin (SBE β CD).